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Zhu G.-H.,Fengxian Central Hospital | Huang C.,Shanghai JiaoTong University | Huang C.,Shanghai Key Laboratory of Pancreatic Diseases | Feng Z.-Z.,Shanghai JiaoTong University | And 3 more authors.
Digestive Diseases and Sciences | Year: 2013

Background: Intratumoral hypoxia and epithelial-mesenchymal transition are involved in tumor invasion and metastasis. Aims: This study investigated the molecular mechanisms that relay the hypoxia signal into the epithelial- mesenchymal transition and metastasis. Methods: Morphology analysis and tumor cell migration and invasion assays were performed to detect phenotypic changes of pancreatic cancer cells under normoxic and hypoxic conditions after lentiviral HIF-1α shRNA transfection. Quantitative reverse transcription polymerase chain reaction, western blot, and immunohistochemistry were used to detect gene expression in pancreatic cancer cell lines and tissues or normal pancreatic tissues. Luciferase, gel shift, and ChIP assays were used to assess gene regulation. Results: Under hypoxic conditions, these tumor cells underwent typical morphological and molecular changes to epithelial-mesenchymal transition. Moreover, Snail expression was induced by hypoxic conditions and was regulated by HIF-1α expression at the transcriptional level through HIF-1α-binding to the second site of hypoxia-responsive elements of the Snail gene promoter. In addition, Snail expression was associated with HIF-1α expression in pancreatic cancer tissues, and expression of both was associated with tumor metastasis and poor patient survival. Conclusions: Our study provides key evidence that HIF-1α and Snail are responsible for hypoxia-induced metastasis phenotypes in pancreatic cancer and that HIF-1α and Snail expression can be used as biomarkers to predict tumor metastasis and patient survival. © 2013 Springer Science+Business Media New York. Source

Jiao F.,Shanghai Key Laboratory of Pancreatic Diseases | Hu H.,Shanghai Key Laboratory of Pancreatic Diseases | Yuan C.,First Peoples Hospital | Wang L.,Shanghai Key Laboratory of Pancreatic Diseases | And 3 more authors.
Oncology Reports | Year: 2014

Pancreatic cancer is one of the most aggressive solid malignancies with a dismal survival rate. Recent studies have shown that high expression levels of long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript-1 (MALAT-1) correlate with several solid tumors. However, the underlying molecular mechanisms and its clinical significance in pancreatic cancer remain to be elucidated. In the present study, our results showed that MALAT-1 expression levels were upregulated in pancreatic cancer tissues compared with adjacent noncancerous controls. Consistently, higher expression level of MALAT-1 was found in all seven pancreatic cancer cell lines relative to the human pancreatic ductal epithelial cell. Further function analysis revealed that downregulation of MALAT-1 could inhibit tumor cell proliferation and decrease cell migration and invasion in vitro. The underlying mechanisms are possibly involved in inducing G2/M cell cycle arrest, promoting cell apoptosis, suppressing epithelial-mesenchymal transition and reducing cancer stem-like properties. In conclusion, this study indicated that MALAT-1 may serve as an oncogenic lncRNA that is involved in malignancy phenotypes of pancreatic cancer. Therefore, it may be used as a potential therapeutic target. Source

Jiao F.,Shanghai JiaoTong University | Jiao F.,Shanghai Key Laboratory of Pancreatic Diseases | Hu H.,Shanghai JiaoTong University | Han T.,Shanghai JiaoTong University | And 6 more authors.
Oncotarget | Year: 2016

Previous studies showed that aberrant CDH1 or/and HDAC3 localization is essential for the progression of some human cancers. Here, we investigate the prognostic significance of aberrant CDH1 and HDAC3 localization in 84 pancreatic cancer patients. Our results show that increases in both membrane and cytoplasmic CDH1 correlate with lymph node metastasis (P = 0.026 and P < 0.001, respectively) and clinical stage (P = 0.020 and P < 0.001, respectively). Increased nuclear HDAC3 correlates with lymph node metastasis (P < 0.001) and advanced clinical stage (P < 0.001), but increased cytoplasmic HDAC3 does not (P > 0.05). Multivariate analysis showed that nuclear HDAC3 and cytoplasmic CDH1 (P = 0.001 and P = 0.010, respectively), as well as tumor differentiation (P = 0.009) are independent prognostic factors. Most importantly, patients with high co-expression of nuclear HDAC3 and cytoplasmic CDH1 had shorter survival times (P < 0.001), more frequent lymph node metastasis (P < 0.001), and advanced clinical stage (P < 0.001). Our studies provide convincing evidence that nuclear HDAC3 and cytoplasmic CDH1 have independent prognostic value in pancreatic cancer and provide novel targets for prognostic therapeutics. Source

Han T.,Shanghai JiaoTong University | Han T.,Shanghai Key Laboratory of Pancreatic Diseases | Jiao F.,Shanghai JiaoTong University | Jiao F.,Shanghai Key Laboratory of Pancreatic Diseases | And 7 more authors.
Oncotarget | Year: 2016

Enhancer of zeste homolog 2 (EZH2) is an essential component of the polycomb repressive complex 2 (PRC2), which is required for epigenetic silencing of target genes, including those affecting cancer progression. Its role in pancreatic cancer remains to be clarified; therefore, we investigated the effects of aberrantly expressed EZH2 on pancreatic cancer. We found that EZH2 expression is up-regulated in pancreatic cancer tissues and positively correlated with lymph node metastasis and advanced clinical stage in pancreatic cancer patients. EZH2 knockdown in pancreatic cancer cell lines inhibited cell migration and invasion, but did not alter cell proliferation. Silencing of EZH2 also increased E-cadherin expression in vitro, and E-cadherin expression was inversely correlated with EZH2 expression in pancreatic cancer tissue samples. Patients with high EZH2 and low E-cadherin expression had the worst prognosis. RIP and ChIP assays suggest that EZH2 is recruited to the E-cadherin promoter by the long non-coding RNA, MALAT-1 (metastasis associated in lung adenocarcinoma transcript 1), where it represses E-cadherin expression. Our results show that EZH2-based therapies may be an option for the treatment of pancreatic cancer. Source

Cui J.,Shanghai JiaoTong University | Cui J.,University of Houston | Cui J.,Shanghai Key Laboratory of Pancreatic Diseases | Quan M.,University of Houston | And 15 more authors.
Medical Oncology | Year: 2015

Lactate dehydrogenase B (LDHB) is widely expressed in adult somatic tissue and is one of the two subunits of lactate dehydrogenase, which is the key glycolytic enzyme and catalyzes the interconversion of pyruvate and lactate. However, the roles of LDHB in glycolysis and tumor progression were obscure in different types of cancer. Here, we determined the roles of LDHB in pancreatic cancer development and progression. We found suppressed expression of LDHB in pancreatic cancer which was due to promoter hypermethylation and deceased expression of LDHB led to glycolytic transition. Functional analysis revealed that suppressed expression of LDHB promoted pancreatic cancer cells proliferation, invasion, and migration in hypoxia. Thus, LDHB might function as a suppressor of glycolysis and suppressed pancreatic cancer progression. © 2015, Springer Science+Business Media New York. Source

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