[Show abstract][Hide abstract] ABSTRACT: CXCR1, a receptor for CXCL8/IL-8, has recently been demonstrated to be associated with cancer stem cell (CSC) populations in certain types of human cancers. However, the effect of CXCR1 on CSC and its prognostic value in human pancreatic cancer remain unknown. In this study, we evaluated the expression of CXCR1 in human pancreatic duct adenocarcinoma (PDAC) and found that positive CXCR1 expression correlated with lymph node metastasis (P = 0.017) and a poor survival rate (HR, 3.748; 95% CI, 1.822 to 7.712; P < 0.001) in patients with PDAC. In addition, we identified significant positive correlations between CXCR1 and CD44 (P = 0.002) and CD133 (P = 0.017). Further functional studies confirmed that IL-8 addition increased sphere formation, CSC populations, and cell invasion of pancreatic cancer cells and that these effects could be reversed by antagonizing CXCR1 with a CXCR1-specific antibody. Therefore, our study demonstrated that the IL-8/CXCR1 axis is associated with the CSC-like properties of pancratic cancer cells and prognosis in human pancreatic cancer. This suggested a way of targeting pancreatic CSCs by disrupting IL-8/CXCR1 axis.
[Show abstract][Hide abstract] ABSTRACT: The transforming growth factor-β (TGF-β) signaling pathway is believed to contribute to carcinoma development by increasing cell invasiveness and metastasis and inducing the epithelial-to-mesenchymal transition (EMT). Protein phosphatase PPM1A has been reported to dephosphorylate TGF-β-activated Smad2/3, thus inhibiting the TGF-β signaling pathway. In this study, we investigated the role of PPM1A in bladder cancer. PPM1A protein expression was analyzed in 145 bladder cancer specimens. The loss of PPM1A expression was predictive of poor survival and high muscle-invasiveness. PPM1A was more commonly deficient among muscle-invasive relapse samples compared to primary tumors in twenty paired bladder cancer tissues. Functional studies indicated that blockade of PPM1A through lentivirus-mediated RNA interference significantly promoted urinary bladder cancer (BCa) cell motility, the EMT in vitro and metastasis in vivo, and these effects were dependent on the TGF-β/Smad signaling pathway. The increase in p-Smad2/3 induced by TGF-β1 correlated with the degree of PPM1A depletion in BCa cells, which resulted in an altered expression profile of TGF-β-inducible genes. The correlations between PPM1A and biomarkers related to the TGF-β signaling pathway and tumor invasion were also detected in BCa samples. These results demonstrate that loss of PPM1A is associated with the development of tumor invasion in bladder cancer patients.
[Show abstract][Hide abstract] ABSTRACT: Tumor resistance to radiation is a challenge to treatment of patients with pancreatic cancer. Improving our understanding of the mechanisms of radioresistance could lead to strategies to increase patients' response to therapy. We investigated the roles of microRNAs (miRNAs) involved in radioresistance of pancreatic cancer cells.
We established radioresistant pancreatic cancer cell lines and used array analysis to compare levels of different miRNAs between radioresistant cell lines and the parental cell lines from which they were derived. We transfected pancreatic cancer cells with miRNA mimics or inhibitors and evaluated their effects on cell radiosensitivity using a clonogenic survival assay. The effects of miRNA on autophagy were determined by transmission electron microscopy and immunoblot analysis. We used a luciferase reporter assay to identify mRNA targets of specific miRNAs.
Radioresistant pancreatic cancer cells had reduced levels of the miRNA MIR23B and increased autophagy, compared with cells that were not radioresistant. Overexpression of MIR23B inhibited radiation-induced autophagy, whereas an inhibitor of MIR23B promoted autophagy in pancreatic cancer cells. Overexpression of MIR23B sensitized pancreatic cancer cells to radiation. The target of MIR23B, ATG12, was overexpressed in radioresistant cells; levels of ATG12 protein correlated with the occurrence of autophagy. Expression of MIR23B blocked radiation-induced autophagy and sensitized pancreatic cancer cells to radiation. We observed an inverse correlation between level of MIR23B and autophagy in human pancreatic cancer tissue samples.
In pancreatic cancer cells, reduced levels of the miRNA MIR23B increase levels of ATG12 and autophagy to promote radioresistance. MIR23B might be used to increase the sensitivity of pancreatic cancer cells to radiation therapy.
No preview · Article · Aug 2013 · Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: miR-21 expression in cancer tissue has been reported to be associated with the clinical outcome and activity of gemcitabine in pancreatic cancer. However, resection is possible in only a minority of patients due to the advanced stages often present at the time of diagnosis, and safely obtaining sufficient quantities of pancreatic tumor tissue for molecular analysis is difficult at the unresectable stages. In this study, we investigated whether the serum level of miR-21 could be used as a predictor of chemosensitivity. We tested the levels of serum miR-21 in a cohort of 177 cases of advanced pancreatic cancer who received gemcitabine-based palliative chemotherapy. We found that a high level of miR-21 in the serum was significantly correlated with a shortened time-to-progression (TTP) and a lower overall survival (OS). The serum miR-21 level was an independent prognostic factor for both the TTP and the OS (HR 1.920; 95% CI, 1.274-2.903, p = 0.002 for TTP and HR 1.705; 95% CI, 1.147-2.535, p = 0.008 for OS). The results from a functional study showed that gemcitabine exposure down-regulated miR-21 expression and up-regulated FasL expression. The increased FasL expression following gemcitabine treatment induced cancer cell apoptosis, whereas the ectopic expression of miR-21 partially protected the cancer cells from gemcitabine-induced apoptosis. Additionally, we confirmed that FasL was a direct target of miR-21. Therefore, the serum level of miR-21 may serve as a predictor of chemosensitivity in advanced pancreatic cancer. Additionally, we identified a new mechanism of chemoresistance mediated by the effects of miR-21 on the FasL/Fas pathway.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To investigate whether there is a difference between urachal and non-urachal adenocarcinomas in terms of patient survival and to determine the significant prognostic factors.
Thirty-four patients with histologically proven adenocarcinoma of the urinary bladder were treated at Huashan hospital between 1999 and 2010. 13 cases were excluded, including 12 patients with metastatic involvement from gastrointestinal or reproductive tracts and one without follow-up data after the initial consultation. Life tables, Kaplan-Meier, Cox regression analysis and log-rank test were used.
The difference between patients with urachal adenocarcinoma and patients with non-urachal adenocarcinoma was not statistically significant using the Kaplan-Meier estimates (P = 0.0763). Clinical stage had a significant influence on survival (P = 0.0320, Fig. 2). Patients with surgical resection including partial and radical cystectomy did not have a better prognosis (P = 0.7992, Fig. 3). However, the difference is statistically significant between patients who received partial cystectomy and patients who received radical cystectomy (P = 0.0123, Fig. 4).
Survival of Patients with adenocarcinoma is correlated with clinical stage. Patients with urachal adenocarcinoma and non-urachal adenocarcinoma may have similar survival outcome. Tumor stage was a highly significant predictor of outcome (P = 0.0320). Surgical resection seems to be more important than chemotherapy in the cases of adenocarcinoma of the urinary bladder. We are in favor of radical cystectomy for all patients.
No preview · Article · Oct 2012 · International Urology and Nephrology
[Show abstract][Hide abstract] ABSTRACT: To investigate alterations of DMBT1 in prostate cancer and determine the correlation of its alterations to the clinicopathologic features of prostate cancer. DMBT1 has been proposed as a candidate tumor suppressor gene for epithelial cancer.
The alterations of DMBT1 expression after treatment with DNA methyltransferase inhibitor in 2 prostate cancer cell lines (LNCaP and PC-3) were analyzed by genome microarray and real-time polymerase chain reaction (PCR). A total of 36 prostate cancer tissues and 16 benign prostatic tissues were evaluated with reverse transcription-PCR, Western blot, and immunohistochemistry for DMBT1 expression.
Treatment with 5-aza-2'-deoxycytidine reactivated expression of DMBT1 in PC3 cells, but not in LNCaP cells. Downregulation or loss of DMBT1 mRNA and protein expression was observed in prostate cancer, but not in benign tissues. Immunostaining analysis showed DMBT1 protein was absent in 14 cancer samples with Gleason score of 8-10 and weakly stained in 16 cancer samples with Gleason score of 4-7, compared with strong immunostaining in all 15 benign prostatic tissues. Loss of DMBT1 expression was correlated with local invasion (P = .048) and bone metastasis (P = .039) but was not correlated with patient age, prostate-specific antigen level, or tumor grade at diagnosis.
Our study provides evidence that loss of DMBT1 expression is associated with prostate cancer, suggesting that DMBT1 may function as a tumor suppressor gene in prostate carcinogenesis.
[Show abstract][Hide abstract] ABSTRACT: Ski used to be defined as an oncogene that contributes to the resistance of tumor cells to transforming growth factor-beta (TGF-beta)-induced growth arrest. As TGF-beta has a dual effect on tumor growth with both tumor-suppressing and -promoting activity depending on the stage of carcinogenesis and the cell type, the precise role of Ski in carcinogenesis remains unclear. In this study, we show that downregulation of Ski through lentivirus-mediated RNA interference decreases tumor growth both in vitro and in vivo, yet promotes cell invasiveness in vitro, and lung metastasis in vivo in the pancreatic cancer cell line SW1990, which contain wild-type Smad4 expression, and the BxPC3 cell line, which is Smad4 deficient. We also show that the downregulation of Ski increases TGF-beta-induced transcriptional activity, which is associated with increased TGF-beta-dependent Smad2/3 phosphorylation, and results in an altered expression profile of TGF-beta-inducible genes involved in metastasis, angiogenesis and cell proliferation and epithelial-mesenchymal transition. Immunohistochemical analysis of specimens from 71 patients with pancreatic adenocarcinoma showed a significant association between overexpression of Ski and decreased patient survival time (P = 0.0024). Our results suggest that Ski may act as a tumor proliferation-promoting factor or as a metastatic suppressor in human pancreatic cancer.
[Show abstract][Hide abstract] ABSTRACT: To investigate the role of the Fas/Fas ligand (Fas/FasL) system in testicular toxicity induced by epirubicin (Epi) and to correlate the system with the serum levels of soluble Fas and Fas ligand (sFas/sFasL), epirubicin was intraperitoneally administered to male Sprague-Dawley male rats at doses of 1.2mg/kg once a week for 10 weeks, and genital organ weights and histopathology were examined. Fas and FasL expression in rat testis were examined by immunohistochemistry. Apoptosis was assessed by TUNEL assay. Expression levels of Fas and FasL were analyzed by RT-PCR and Western blotting. Serum sFas/sFasL levels were determined by ELISA. The results show that the testicular toxicity of Epi involved germ cell apoptosis. Fas and FasL protein expression levels were markedly increased in Epi-treated rat testes, as was expression of sFasL. In particular, increasing serum sFasL levels were positively correlated with elevated expression levels of FasL and sFasL in the testes of Epi-treated rats, revealing serum sFasL to be a promising marker of testicular toxicity after cytotoxic chemotherapy.
No preview · Article · May 2009 · Toxicology Letters
[Show abstract][Hide abstract] ABSTRACT: Whether Smad7 acts as a tumor proliferation promoting factor or as a metastatic suppressor in human pancreatic cancer remains unclear. This study aims to determine the prognostic value of Smad7 in patients with pancreatic adenocarcinoma.
Surgical specimens obtained from 71 patients with pancreatic adenocarcinoma were immunohistochemically assessed for Smad7, Ki-67, MMP2, CD34, and Smad4 expression. The relationship between Smad7 expression and the clinicopathological characteristics of patients with pancreatic adenocarcinoma were also evaluated.
Fifty-one of 71 specimens (71.8%) were Smad7 positive and 20 specimens were Smad7 negative. Negative expression of Smad7 correlated with lymph node metastasis, liver metastasis after surgery, and a poor survival rate (P = 0.0004, 0.0044, and 0.0003, respectively). We also found an inverse correlation between the expression of Smad7 and MMP2 (P = 0.0189). Multivariate analysis revealed that Smad7 expression was an independent prognostic factor [hazard ratio (HR) 0.3902; 95% confidence interval (CI) 0.1839-0.8277; P = 0.0142]. Furthermore, in both Smad4-negative and Smad4-positive groups, survival of patients with Smad7-positive tumors was significantly better than those with Smad7-negative tumors (both P < 0.0001).
We conclude that low-level expression of Smad7 in pancreatic cancer is significantly associated with lymph node metastasis, high MMP2 expression, and poor prognosis.
No preview · Article · Apr 2009 · Annals of Surgical Oncology