JMJD3 expression is an independent prognosticator in patients with esophageal squamous cell carcinoma.

BACKGROUND: The Jumonji-domain containing 3 has diverse roles in multiple cancers. Here, we investigated its prognostic significance in esophageal squamous cell carcinoma. METHODS: By using immunohistochemistry, the Jumonji-domain containing 3 expression was examined in 109 surgically resected esophageal squamous cell carcinomas and correlated with treatment outcome. The functional role of Jumonji-domain containing 3 in esophageal squamous cell carcinoma cells was determined by Jumonji-domain containing 3-mediated small interfering ribonucleic acid. RESULTS: Univariate analysis showed that Jumonji-domain containing 3 overexpression was associated with inferior overall survival (P = .004) and disease-free survival (P = .002). In a multivariate comparison, Jumonji-domain containing 3 overexpression remained independently associated with worse overall survival (P = .017, hazard ratio = 1.898) and disease-free survival (P = .011, hazard ratio = 1.901). The 5-year overall and disease-free survival rates were 66% and 58% in patients with a low expression of Jumonji-domain containing 3 and 34% and 27% in patients with overexpression of Jumonji-domain containing 3. Silencing Jumonji-domain containing 3 in esophageal squamous cell carcinoma cells inhibited cell growth rate and bromodeoxyuridine incorporation ability. In contrast, a gain of function of Jumonji-domain containing 3 promoted esophageal squamous cell carcinoma cell proliferation. Furthermore, Jumonji-domain containing 3 expression contributes to Ras/MEK pathway. CONCLUSION: Jumonji-domain containing 3 overexpression was independently associated with poor prognosis in patients with esophageal squamous cell carcinoma. In vitro, Jumonji-domain containing 3 expression regulated esophageal squamous cell carcinoma cell growth. These results may further elucidate the role of Jumonji-domain containing 3 in esophageal squamous cell carcinoma and provide a potential new therapeutic approach for patients with esophageal squamous cell carcinoma.

SIRT1 overexpression is an independent prognosticator for patients with esophageal squamous cell carcinoma.

BACKGROUND: Sirtuin 1 (SIRT1) regulates DNA repair and metabolism by deacetylating target proteins. SIRT1 may be oncogenic because its overexpression has been detected in many cancers. The aim of the present study was to clarify the prognostic role of SIRT1 in patients with esophageal squamous cell carcinoma (ESCC) and evaluate the effect of SIRT1 inhibitor in vitro. METHODS: The expression of SIRT1 was evaluated immunohistochemically in 155 surgically resected ESCC and the staining results were evaluated semiquantitatively by the Immunoreactive Scoring System. The clinical features and treatment outcome were analyzed. The effect of SIRT1 inhibitor, SIRT 1 inhibitor IV, (S)-35, was investigated in vitro on ESCC cell lines. RESULTS: The expression of SIRT1 on ESCC did not correlate with age, gender, tumor location, stage, T classification, N classification, surgical margin or histology. Univariate analysis showed that SIRT1 overexpression was associated with inferior overall survival (P = 0.004) and disease-free survival (P = 0.004). In multivariate comparison, SIRT1 overexpression remained independently associated with worse overall survival (P = 0.009, hazard ratio = 1.776) and disease-free survival (P = 0.017, hazard ratio = 1.642). In cell lines, SIRT1 inhibitor inhibited ESCC growth. CONCLUSIONS: Our study suggests that SIRT1 overexpression is an independent prognosticator for patients with ESCC and the SIRT1 inhibitor suppressed cell proliferation of ESCC cell lines. Our findings suggest that inhibition of SIRT1 signaling may be a promising novel target for ESCC.

The Prognostic Significance of Histone Demethylase UTX in Esophageal Squamous Cell Carcinoma.

The dysregulation of the ubiquitously transcribed TPR gene on the X chromosome (UTX) has been reported to be involved in the oncogenesis of several types of cancers. However, the expression and significance of UTX in esophageal squamous cell carcinoma (ESCC) remains largely undetermined. Immunohistochemistry was performed in 106 ESCC patients, and correlated with clinicopathological features and survival. The functional role of UTX in ESCC cells was determined by UTX-mediated siRNA. Univariate analyses showed that high UTX expression was associated with superior overall survival (OS, p = 0.011) and disease-free survival (DFS, p = 0.01). UTX overexpression was an independent prognosticator in multivariate analysis for OS (p = 0.013, hazard ratio = 1.996) and DFS (p = 0.009, hazard ratio = 1.972). The 5-year OS rates were 39% and 61% in patients with low expression and high expression of UTX, respectively. Inhibition of endogenous UTX in ESCC cells increased cell viability and BrdU incorporation, and decreased the expression of epithelial marker E-cadherin. Immunohistochemically, UTX expression was also positively correlated with E-cadherin expression. High UTX expression is independently associated with a better prognosis in patients with ESCC and downregulation of UTX increases ESCC cell growth and decreases E-cadherin expression. Our results suggest that UTX may be a novel therapeutic target for patients with ESCC.

Prognostic significance and function of mammalian target of rapamycin in tongue squamous cell carcinoma.

Despite improvement in preoperative imaging, surgical technique, and adjuvant therapy, the prognosis of patients with tongue squamous cell carcinoma (SCC) is still unsatisfactory. The mammalian target of rapamycin (mTOR) play a key role in the regulation of tumor cell proliferation and survival. However, the significance of mTOR on the prognosis of tongue SCC remains largely undefined. In the present study, immunohistochemistry was performed to evaluate the expression of phosphorylated mTOR (p-mTOR) in 160 surgically resected tongue SCC, and correlated with survival. Univariate analysis revealed that p-mTOR overexpression (P = 0.006) was associated with inferior overall survival. In multivariate comparison, p-mTOR overexpression (P = 0.002, hazard ratio = 2.082) remained independently associated with worse overall survival. In vitro study, tongue cancer cells treated with everolimus, the specific mTOR inhibitor, or transfected with mTOR-mediated siRNAs dramatically attenuated the abilities of cell proliferation by MTT and BrdU assays. In 4-NQO-induced tongue cancer murine model, mTOR inhibitors significantly decreased the incidence of tongue SCC. In conclusion, p-mTOR overexpression was independently associated with poor prognosis of patients with tongue SCC. In vitro and vivo, mTOR inhibition showed the promising activity in tongue SCC. Our results suggest that inhibition of mTOR signaling pathway may be a novel therapeutic target for tongue SCC.

Angiotensin II type I receptor (AT1R) is an independent prognosticator of esophageal squamous cell carcinoma and promotes cells proliferation via mTOR activation.

BACKGROUND: The aim of this study was to investigate the effects of the angiotensin II/ angiotensin II type I receptor (AT1R) and angiotensin II type II receptor (AT2R) signaling pathway in esophageal squamous cell carcinoma (ESCC). METHODS: Immunohistochemistry was performed to evaluate the expression levels of AT1R and AT2R in tissues from 152 surgically resected ESCC patients, and those expression levels were then correlated with treatment outcomes. The angiotensin II/AT1R/AT2R signaling pathway and its biological effects in the context of ESCC were investigated in vitro and in vivo. RESULTS: In human samples, AT1R overexpression was univariately associated with inferior overall survival and remained multivariately independent (hazard ratio=1.812). In vitro, angiotensin II stimulated the growth of ESCC cells in a dose-dependent manner. Treatment with irbesartan or AT1R-RNAi knockdown but not treatment with PD123319 significantly decreased the level of angiotensin II-induced ESCC cell proliferation. Angiotensin II also caused mTOR activation in a dose-dependent manner, and everolimus or mTOR-RNAi knockdown significantly suppressed the level of angiotensin II-induced ESCC cell proliferation. Furthermore, AT1R-RNAi knockdown suppressed the activation of mTOR. Clinically, AT1R expression was also correlated with phosphorylated mTOR expression. In a xenograft model, local angiotensin II injection enhanced tumor growth, and this effect could be decreased by treatment with irbesartan or everolimus. In a 4-NQO-induced-ESCC murine model, irbesartan significantly decreased the incidence of esophageal tumor. CONCLUSIONS: These findings suggest that AT1R overexpression is an independent adverse prognosticator for patients with ESCC and that angiotensin II/AT1R signaling stimulates ESCC growth, in part through mTOR activation.

Phosphorylated p70S6K expression is an independent prognosticator for patients with esophageal squamous cell carcinoma.

BACKGROUND: Although marked improvements have been made in surgical technique and chemoradiotherapy, the prognosis for patients with esophageal squamous cell carcinoma (ESCC) is still unsatisfactory. The mammalian target of rapamycin (mTOR) and its downstream signaling, p70 ribosomal S6 protein kinase (p70S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), seem to play central roles in the regulation of cancer cell proliferation and survival. The significance of mTOR and its downstream targets, p70S6K and 4E-BP1, on the prognosis of ESCC remains uncertain, but this pathway is of particular concern because effective inhibitors are already available. METHODS: Immunohistochemistry performed to evaluate the expression of phosphorylated mTOR (p-mTOR), phosphorylated p70S6K (p-p70S6K), phosphorylated 4E-binding protein 1 (p-4E-BP1), and Ki-67 using 105 surgically resected ESCC correlated with treatment outcome. The effect of the mTOR signaling pathway inhibitor everolimus on ESCC cell lines were investigated in vitro by the 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and in vivo by a nude mouse xenograft model. RESULTS: Univariate analysis showed that p-mTOR overexpression (P = .022), p-p70S6K overexpression (P = .002), and Ki-67 labeling index >50% (P = .045) were associated with inferior overall survival (OS). In a multivariate comparison, p-p70S6K overexpression (P = .001; hazard ratio, 2.247) remained independently associated with worse OS. In cell lines and the xenograft model, everolimus significantly inhibited ESCC growth. CONCLUSION: Overexpression of p-p70S6K is associated independently with a poor prognosis among patients with ESCC. The mTOR signaling pathway inhibitor everolimus can inhibit ESCC growth in vitro and in vivo. Our findings suggest that inhibition of mTOR signaling pathway may be a promising novel target for ESCC.

A comparative study of isolated and metachronous oesophageal squamous cell carcinoma with antecedent upper aerodigestive tract cancer.

OBJECTIVES: Metachronous oesophageal squamous cell carcinoma (OSCC) has been increasing in long-term survivors of upper aerodigestive tract (UADT) cancers in recent years, but the treatment of such cases is not well established. The aim of this study was to compare the prognosis between patients with metachronous OSCC who had antecedent UADT cancers and patients with isolated OSCC. METHODS: From January 1995 to December 2009, we retrospectively compared the data from 84 patients with metachronous OSCC who had antecedent UADT cancers (metachronous group) with the data from 527 patients with isolated OSCC (isolated group) according to their treatment modalities at Kaohsiung Chang Gung Memorial Hospital. RESULTS: Overall, the metachronous group had significantly (P = 0.03) worse overall survival than the isolated group. For patients receiving surgery or preoperative chemoradiotherapy followed by surgery, the overall survival rates and incidence of postoperative complications were not significantly different. For patients receiving definite chemoradiotherapy or radiotherapy alone, the metachronous group had significantly (P = 0.02) inferior overall survival compared with the isolated group. CONCLUSIONS: Offering a radical approach for the treatment of patients with metachronous OSCC who had antecedent UADT cancers is justifiable, with survival rates similar to those of patients with isolated OSCC.

Is there a role of whole-body bone scan in patients with esophageal squamous cell carcinoma.

BACKGROUND: Correct detection of bone metastases in patients with esophageal squamous cell carcinoma is pivotal for prognosis and selection of an appropriate treatment regimen. Whole-body bone scan for staging is not routinely recommended in patients with esophageal squamous cell carcinoma. The aim of this study was to investigate the role of bone scan in detecting bone metastases in patients with esophageal squamous cell carcinoma. METHODS: We retrospectively evaluated the radiographic and scintigraphic images of 360 esophageal squamous cell carcinoma patients between 1999 and 2008. Of these 360 patients, 288 patients received bone scan during pretreatment staging, and sensitivity, specificity, positive predictive value, and negative predictive value of bone scan were determined. Of these 360 patients, surgery was performed in 161 patients including 119 patients with preoperative bone scan and 42 patients without preoperative bone scan. Among these 161 patients receiving surgery, 133 patients had stages II + III disease, including 99 patients with preoperative bone scan and 34 patients without preoperative bone scan. Bone recurrence-free survival and overall survival were compared in all 161 patients and 133 stages II + III patients, respectively. RESULTS: The diagnostic performance for bone metastasis was as follows: sensitivity, 80%; specificity, 90.1%; positive predictive value, 43.5%; and negative predictive value, 97.9%. In all 161 patients receiving surgery, absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival (P = 0.009, univariately). In multivariate comparison, absence of preoperative bone scan (P = 0.012, odds ratio: 5.053) represented the independent adverse prognosticator for bone recurrence-free survival. In 133 stages II + III patients receiving surgery, absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival (P = 0.003, univariately) and overall survival (P = 0.037, univariately). In multivariate comparison, absence of preoperative bone scan was independently associated with inferior bone recurrence-free survival (P = 0.009, odds ratio: 5.832) and overall survival (P = 0.029, odds ratio: 1.603). CONCLUSIONS: Absence of preoperative bone scan was significantly associated with inferior bone recurrence-free survival, suggesting that whole-body bone scan should be performed before esophagectomy in patients with esophageal squamous cell carcinoma, especially in patients with advanced stages.

Pre-treatment maximal oesophageal wall thickness is independently associated with response to chemoradiotherapy in patients with T3-4 oesophageal squamous cell carcinoma.

OBJECTIVES: Combined chemoradiotherapy with or without surgery is frequently performed as a curative treatment in patients with T3-4 locally advanced oesophageal squamous cell carcinoma. Computed tomography (CT) is frequently performed before and after chemoradiotherapy. The aim of this study is to evaluate the utility of the oesophageal wall thickness on CT scans to predict the response to chemoradiotherapy and the treatment outcome in patients with T3-4 locally advanced oesophageal squamous cell carcinoma. METHODS: Ninety-six patients with T3-4 locally advanced oesophageal squamous cell carcinoma, who were treated with neoadjuvant chemoradiotherapy followed by surgery between 1998 and 2008 at the Kaohsiung Chang Gung Memorial Hospital, were retrospectively reviewed. CT scans before and after chemoradiotherapy were available for 93 patients. Of these 93 patients, 24% (22 of 93) achieved a pathologically complete response (pCR). The measurement of the maximal dimension of the oesophageal wall thickness on CT scans before (pre) and after (post) chemoradiotherapy was performed retrospectively, and correlated with the response to chemoradiotherapy and patients' outcome. The percentage decrease of maximal oesophageal wall thickness after chemoradiotherapy was determined by the formula: [(pre -post)/pre] 100. RESULTS: Pre- and post-chemoradiotherapy maximal oesophageal wall thicknesses were significantly correlated with pCR, but the percent decrease of oesophageal wall thickness after chemoradiothrapy was not. Logistic models showed that pre-chemoradiotherapy maximal oesophageal wall thickness ≥20 mm was independently associated with response to chemoradiotherapy. For patients with pre-chemoradiotherapy maximal oesophageal wall thickness ≥20 mm, 91% did not achieve pCR after chemoradiotherapy. Univariate analyses demonstrated that a pre-chemoradiotherapy maximal oesophageal wall thickness ≥20 mm, T4 disease and positive regional lymph nodes (N stage) were predictive of inferior disease-free survival. In a multivariate comparison, pre-chemoradiotherapy maximal oesophageal wall thickness ≥20 mm represented an independent adverse prognosticator for disease-specific survival and disease-free survival. CONCLUSIONS: Most of the T3-4 locally advanced oesophageal squamous cell carcinoma patients with pre-treatment maximal oesophageal wall thickness ≥20 mm did not achieve pCR after chemoradiotherapy. Thus, oesophgectomy may be considered in advance in this group of patients. Pre-treatment maximal oesophageal wall thickness is of independent prognostic value in patients with T3-4 locally advanced oesophageal squamous cell carcinoma who receive neoadjuvant chemotheradiotherapy.