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pancreatic cancer EMT

Kishore Polireddy, Ruochen Dong, Peter R McDonald, Tao Wang, Brendan Luke, Ping Chen, Melinda Broward, Anuradha Roy, Qi Chen
BACKGROUND: Pancreatic cancer has an enrichment of stem-like cancer cells (CSCs) that contribute to chemoresistant tumors prone to metastasis and recurrence. Drug screening assays based on cytotoxicity cannot identify specific CSC inhibitors, because CSCs comprise only a small portion of cancer cell population, and it is difficult to propagate stable CSC populations in vitro for high-throughput screening (HTS) assays. Based on the important role of cancer cell epithelial-to-mesenchymal transition (EMT) in promoting CSCs, we hypothesized that inhibition of EMT can be a useful strategy for inhibiting CSCs, and therefore a feasible approach for HTS can be built for identification of CSC inhibitors, based on assays detecting EMT inhibition...
2016: PloS One
Yuan Seng Wu, Ivy Chung, Won Fen Wong, Atsushi Masamune, Maw Shin Sim, Chung Yeng Looi
BACKGROUND: We previously showed that pancreatic stellate cells (PSC) secreted interleukin (IL)-6 and promoted pancreatic ductal adenocarcinoma (PDAC) cell proliferation via nuclear factor erythroid 2 (Nrf2)-mediated metabolic reprogramming. Epithelial-mesenchymal transition (EMT) is a key process for the metastatic cascade. To study the mechanism of PDAC progression to metastasis, we investigated the role of PSC-secreted IL-6 in activating EMT and the involvement of Nrf2 in this process...
October 14, 2016: Biochimica et Biophysica Acta
Cuiyue Wang, Zhen Feng, Kaitong Jiang, Xiuli Zuo
Our goal was to determine the roles and regulatory mechanism of microRNA-935 (miR-935) in the progression of pancreatic cancer. The results showed that, compared with normal pancreatic tissues and cells, the expression of miR-935 was markedly upregulated while INPP4A expression was obviously downregulated in pancreatic cancer tissues and PANC-1 cells. After transfection with miR-935 inhibitor, miR-935 was significantly suppressed, and suppression of miR-935 significantly inhibited cell proliferation, suppressed cell migration, and induced cell apoptosis of pancreatic cancer cells...
October 11, 2016: Oncology Research
Lijun Zhao, Dongling Zou, Xueju Wei, Lanlan Wang, Yuanyuan Zhang, Siqi Liu, Yanmin Si, Hualu Zhao, Fang Wang, Jia Yu, Yanni Ma, Guotao Sun
Pancreatic cancer is a highly lethal disease due to its rapid dissemination and resistance to conventional chemotherapy. MicroRNAs (miRNAs) are emerging as novel regulators of chemoresistance, which modulate the expression of drug resistance-related genes. MiRNA-221 has been reported to be associated with chemoresistance in various types of cancer. But the detailed molecular mechanism about miR-221-3p regulating 5-fluorouracil (5-FU) resistance in human pancreatic cancer remains to be clarified. In this study, we investigated the association between miR-221-3p expression and 5-FU sensitivity...
October 10, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Chunxiang Ye, Xiuyun Tian, Guanjun Yue, Liang Yan, Xiaoya Guan, Shan Wang, Chunyi Hao
CD26/DPPIV is a glycosylated transmembrane type II protein and has a multitude of biological functions, while its impact on the malignant phenotypes of cancer cells has not been fully understood. This study aimed to investigate the effect of CD26 on growth and metastasis of pancreatic cancer cells in vitro and in vivo. We found in this study that CD26 expression was higher in cell lines that derived from the metastatic sites than those from the primary tumor sites. In specimens of pancreatic cancer patients, CD26 expression was higher in cancerous tissues than in paired normal tissues...
October 7, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Giuseppina Sannino, Nicole Armbruster, Mona Bodenhöfer, Ursula Haerle, Diana Behrens, Malte Buchholz, Ulrich Rothbauer, Bence Sipos, Christian Schmees
Pancreatic ductal adenocarcinoma (PDAC) has a low overall survival rate, which is approximately 20% during the first year and decreases to less than 6% within five years of the disease. This is due to premature dissemination accompanied by a lack of disease-specific symptoms during the initial stages. Additionally, to date there are no biomarkers for an early prognosis available.A growing number of studies indicate that epithelial to mesenchymal transition (EMT), triggered by WNT-, TGF-β- and other signaling pathways is crucial for the initiation of the metastatic process in PDAC...
October 4, 2016: Oncotarget
Shi Chen, Jiang-Zhi Chen, Jia-Qiang Zhang, Hui-Xin Chen, Mao-Lin Yan, Long Huang, Yi-Feng Tian, Yan-Lin Chen, Yao-Dong Wang
The epithelial-mesenchymal transition (EMT) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) development and progression. TWIST activated by intra-tumoral hypoxia functions to promote the EMT. We hypothesized that TWIST and the downstream gene pathway could mediate PDAC progression under hypoxia. Therefore, 90 PDAC tissue specimens were immunostained for TWIST and other proteins. Pancreatic cancer cell lines were used for in vitro experiments and nude mice were used to confirm the in vivo data...
September 28, 2016: Cancer Letters
Raj Kumar Verma, Wei Yu, Anju Shrivastava, Sharmila Shankar, Rakesh K Srivastava
Activation of sonic hedgehog (Shh) in cancer stem cell (CSC) has been demonstrated with aggressiveness of pancreatic cancer. In order to enhance the biological activity of α-mangostin, we formulated mangostin-encapsulated PLGA nanoparticles (Mang-NPs) and examined the molecular mechanisms by which they inhibit human and KC mice (Pdx(Cre);LSL-Kras(G12D)) pancreatic CSC characteristics in vitro, and pancreatic carcinogenesis in KPC (Pdx(Cre);LSLKras(G12D);LSL-Trp53(R172H)) mice. Mang-NPs inhibited human and Kras(G12D) mice pancreatic CSC characteristics in vitro...
2016: Scientific Reports
Hardik Mody, Sau Wai Hung, Mohammad Al-Saggar, Jazmine Griffin, Rajgopal Govindarajan
: Identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacological inhibitors of Enhancer of Zeste Homolog 2 (EZH2) are emerging as potential histone methylation reversal agents for the treatment of various solid tumors and leukemia; however, the surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms contribute to their anti-tumorigenic effects...
September 13, 2016: Molecular Cancer Research: MCR
Huocong Huang, Robert A Svoboda, Audrey J Lazenby, Jintana Saowapa, Nina Chaika, Ke Ding, Margaret J Wheelock, Keith R Johnson
Pancreatic ductal adenocarcinomas (PDAC) are highly malignant cancers characterized by extensive invasion into surrounding tissues, metastasis to distant organs, and a limited response to therapy. A main feature of PDAC is desmoplasia, which leads to extensive deposition of collagen I. We have demonstrated that collagen I can induce epithelial-mesenchymal transition (EMT) in pancreatic cancer cells. A hallmark of EMT is an increase in the expression of the mesenchymal cadherin N-cadherin. Previously we showed up-regulation of N-cadherin promotes tumor cell invasion and collagen I-induced EMT is mediated by two collagen receptors, alpha2beta1-integrin and discoidin domain receptor 1 (DDR1)...
September 7, 2016: Journal of Biological Chemistry
Han Zhu, Hua Qin, De-Min Li, Jing Liu, Qiu Zhao
The objective of this study was to investigate the effect of silencing gene protein phosphatase 1H (PPM1H) on malignant phenotype of human pancreatic cancer cell line BxPC-3. In order to explore the function of PPM1H in pancreatic cancer cells, real-time PCR and western blotting were used to detect the expression of PPM1H in different pancreatic cancer cell lines. Human pancreatic cancer cell line BxPC-3 was treated with 10 ng/ml TGF-β1 and 200 ng/ml BMP2 for 72 h, respectively, and the mRNA and protein expression levels of PPM1H and EMT-related markers (E-cadherin, vimentin) were detected by real-time PCR and western blotting, respectively...
September 5, 2016: Oncology Reports
L G Kondratyeva, A A Sveshnikova, E V Grankina, I P Chernov, M R Kopantseva, E P Kopantzev, E D Sverdlov
We show characteristic morphological changes corresponding to epithelial-mesenchymal transition (EMT) program fulfillment in PANC1 cell line stimulated with TGFβ1. Our results support downregulation of E-cadherin protein. We show 5- and 28-fold increase in SNAI1 and SNAI2 expression levels and 25- and 15-fold decrease in CDH1 and KRT8 expression levels, respectively, which confirms the EMT-program fulfillment. We demonstrate downregulation of expression of pancreatic master genes SOX9, FOXA2, and GATA4 (2-, 5-, and 4-fold, respectively) and absence of significant changes in HES1, NR5A2, and GATA6 expression levels in the cells stimulated with TGFβ1...
July 2016: Doklady. Biochemistry and Biophysics
Bin Zhou, Hanxiang Zhan, Lamtin Tin, Shanglong Liu, Jianwei Xu, Yanan Dong, Xiaoyu Li, Liqun Wu, Weidong Guo
Pancreatic cancer (PC) is usually lethal because of late diagnosis and early metastasis. Analysis of data from online database showed that TUFT1 is highly expressed in liver metastases of PC, and was associated with shorter overall survival. However, the role of TUFT1 in PC remains unknown. In this study, we show for the first time that TUFT1 is overexpressed in PC tissues compared with adjacent normal pancreas tissues, and TUFT1 expression is significantly associated with lymph node metastasis and advanced PC stage (P <0...
August 24, 2016: Cancer Letters
H M Tang, K T Kuay, P F Koh, M Asad, T Z Tan, V Y Chung, S C Lee, J P Thiery, Ry-J Huang
Epithelial-mesenchymal transition (EMT), a crucial mechanism in development, mediates aggressiveness during carcinoma progression and therapeutic refractoriness. The reversibility of EMT makes it an attractive strategy in designing novel therapeutic approaches. Therefore, drug discovery pipelines for EMT reversal are in need to discover emerging classes of compounds. Here, we outline a pre-clinical drug screening platform for EMT reversal that consists of three phases of drug discovery and validation. From the Phase 1 epithelial marker promoter induction (EpI) screen on a library consisting of compounds being approved by Food and Drug Administration (FDA), Vorinostat (SAHA), a histone deacetylase inhibitor (HDACi), is identified to exert EMT reversal effects by restoring the expression of an epithelial marker, E-cadherin...
2016: Cell Death Discovery
Xiaomin Zhong, Lan Zheng, Jianfeng Shen, Dongmei Zhang, Minmin Xiong, Youyou Zhang, Xinhong He, Janos L Tanyi, Feng Yang, Kathleen T Montone, Xiaojun Chen, Congjian Xu, Andy P Xiang, Qihong Huang, Xiaowei Xu, Lin Zhang
Oncogenic KRAS contributes to malignant transformation, antiapoptosis, and metastasis in multiple human cancers, such as lung, colon, and pancreatic cancers and melanoma. MicroRNAs (miRNAs) are endogenous 18- to 25-nucleotide noncoding small RNAs that regulate gene expression in a sequence-specific manner via the degradation of target mRNAs or inhibition of protein translation. In the present study, using array-based miRNA profiling in IMR90 and MCF10A cells expressing oncogenic KRAS, we identified that the expression of the microRNA 200 (mir-200) family was suppressed by KRAS activation and that this suppression was mediated by the transcription factors JUN and SP1 in addition to ZEB1...
November 1, 2016: Molecular and Cellular Biology
Pratiek N Matkar, Krishna Kumar Singh, Dmitriy Rudenko, Yu Jin Kim, Michael A Kuliszewski, Gerald J Prud'homme, David W Hedley, Howard Leong-Poi
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an intense fibrotic reaction termed tumor desmoplasia, which is in part responsible for its aggressiveness. Endothelial cells have been shown to display cellular plasticity in the form of endothelial-to-mesenchymal transition (EndMT) that serves as an important source of fibroblasts in pathological disorders, including cancer. Angiogenic co-receptor, neuropilin-1 (NRP- 1) actively binds TGFβ1, the primary mediator of EndMT and is involved in oncogenic processes like epithelial-to-mesenchymal transition (EMT)...
August 4, 2016: Oncotarget
Salman B Hosain, Sachin K Khiste, Mohammad B Uddin, Vindya Vorubindi, Catherine Ingram, Sifang Zhang, Ronald A Hill, Xin Gu, Yong-Yu Liu
Missense mutation of tumor suppressor p53, which exhibits oncogenic gain-of-function (GOF), not only promotes tumor progression, but also diminishes therapeutic efficacies of cancer treatments. However, it remains unclear how a p53 missense mutant contributes to induced pluripotency of cancer stem cells (CSCs) in tumors exposed to chemotherapeutic agents. More importantly, it may be possible to abrogate the GOF by restoring wild-type p53 activity, thereby overcoming the deleterious effects resulting from heterotetramer formation, which often compromises the efficacies of current approaches being used to reactivate p53 function...
August 10, 2016: Oncotarget
Toshiyuki Ishiwata
Despite the development of various therapeutic approaches, recurrence and metastasis remain major problems for patients with advanced cancer. Recent studies have shown that cancer stem cells (CSCs) play an important role in cancer aggressiveness. In cancer tissues, a small number of CSCs are able to self-renew and differentiate into heterogeneous cancer cells. CSCs usually remain in the resting phase of the cell cycle and possess efficient drug efflux pathways. Thus, they are resistant to chemoradiotherapy and surviving CSCs contribute to recurrence...
August 10, 2016: Pathology International
Lirong Zhang, Dongqing Wang, Yumei Li, Yanfang Liu, Xiaodong Xie, Yingying Wu, Yuepeng Zhou, Jing Ren, Jianxin Zhang, Haitao Zhu, Zhaoliang Su
BACKGROUND: Tumor metastasis is driven by malignant cells and stromal cell components of the tumor microenvironment. Cancer stem cells (CSCs) are thought to be responsible for metastasis by altering the tumor microenvironment. Epithelial-mesenchymal transition (EMT) processes contribute to specific stages of the metastatic cascade, promoted by cytokines and chemokines secreted by stromal cell components in the tumor microenvironment. C-C chemokine receptor 7 (CCR7) interacts with its ligand, chemokine ligand 21(CCL21), to mediate metastasis in some cancer cells lines...
2016: PloS One
Kishore Polireddy, Qi Chen
Pancreatic cancer is one of the most lethal cancers among all malignances, with a median overall survival of <1 year and a 5-year survival of ~5%. The dismal survival rate and prognosis are likely due to lack of early diagnosis, fulminant disease course, high metastasis rate, and disappointing treatment outcome. Pancreatic cancers harbor a variety of genetic alternations that render it difficult to treat even with targeted therapy. Recent studies revealed that pancreatic cancers are highly enriched with a cancer stem cell (CSC) population, which is resistant to chemotherapeutic drugs, and therefore escapes chemotherapy and promotes tumor recurrence...
2016: Journal of Cancer
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