High-resolution Hi-C maps highlight multiscale 3D epigenome reprogramming during pancreatic cancer metastasis

Abstract Background Pancreatic cancer’s poor prognosis is caused by distal metastasis, which is associated with epigenetic changes. However, the role of the 3D epigenome in pancreatic cancer biology, especially its metastasis, remains unclear. Methods Here, we developed high-resolution 3D epigenomic maps of cells derived from normal pancreatic epithelium, primary and metastatic pancreatic cancer by in situ Hi-C, ChIP-seq, ATAC-seq, and RNA-seq to identify key genes involved in pancreatic cancer metastasis Results We found that A/B compartments, contact domains, and chromatin loops changed significantly in metastatic pancreatic cancer cells, which are associated with epigenetic state alterations. Moreover, we found that upregulated genes, which were located in switched compartments, changed contact domains, and metastasis-specific enhancer-promoter loops, were related to cancer metastasis and poor prognosis of patients with pancreatic cancer. We also found that transcription factors in specific enhancer-promoter loop formation were also associated with metastasis. Finally we demonstrated that LIPC, looped to metastasis-specific enhancers, could promote pancreatic cancer metastasis. Conclusions These results highlight the multiscale 3D epigenome reprogramming during pancreatic cancer metastasis and expand our knowledge of mechanisms of gene regulation during pancreatic cancer metastasis.

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Primary and Metastatic Pancreatic Cancer Cells Exhibit Differential Migratory Potentials

Pancreas ◽

10.1097/mpa.0000000000001459 ◽

2020 ◽

Vol 49 (1) ◽

pp. 128-134

Author(s):

Joo Kyung Park ◽

Thomas Hank ◽

Cally M. Scherber ◽

Keith D. Lillemoe ◽

Carlos Fernández-del Castillo ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Metastatic Pancreatic Cancer ◽

Pancreatic Cancer Cells

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Use of high-resolution fluorescence laparoscopy with fluorophore-conjugated tumor-specific antibodies for the detection of pancreatic cancer metastasis invisible with standard laparoscopy.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.212 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 212-212

Author(s):

Cristiina A. Metildi ◽

Sharmeela Kaushal ◽

Hop S. Tran Cao ◽

Cynthia S. Snyder ◽

Mark A. Talamini ◽

...

Keyword(s):

Pancreatic Cancer ◽

Light Source ◽

Cancer Metastasis ◽

False Negative ◽

Human Pancreatic Cancer ◽

Pancreatic Tumors ◽

Primary Tumors ◽

Led Light ◽

Pancreatic Cancer Cells ◽

Standard Laparoscopy

212 Background: Standard laparoscopy for pancreatic cancer often leads to false negative results, causing understaging of the disease. Improved sensitivity and resolution are necessary. Methods: Orthotopic and carcinomatosis mouse models of human pancreatic cancer were established with red fluorescent protein (RFP)-expressing or non-fluorescent BxPC-3 human pancreatic cancer cells. The mice with orthotopic unlabeled pancreatic cancer were administered Alexa 488- or 555-conjugated anti-CEA by tail-vein injection 2-4 weeks after tumor implantation. Diagnostic laparoscopy was performed with a Stryker L9000 LED light source or X8000 xenon light source 24 hours later. Pancreatic tumors were detected and localized under each light mode. After laparoscopy, intravital images were obtained with the OV-100 and Maestro CRI Small Animal Imaging Systems as positive controls. Tumors were collected for histologic analysis. Results: Fluorescence laparoscopy (FL) with the use of 495-nm excitation filter and an LED light source enabled more rapid and accurate identification and localization of primary tumors and metastases than bright light laparoscopy (BL). The use of fluorescent conjugates antibody-labeled tumors improved the accuracy of staging laparoscopy, increasing the sensitivity from 40% in BL to 96% in FL (p<0.001). FL was sufficiently sensitive to detect sub-millimeter tumor deposits that went undetected under BL. With adjustments to the LED light source, we could simultaneously detect tumor lesions of different fluorescent colors and surrounding structures with minimal autofluorescence. Conclusions: The use of FL and fluorophore-labeled anti-CEA antibodies permits rapid detection and accurate localization of primary and metastatic CEA-expressing human pancreatic cancer, including tumors that were undetectable with BL. The introduction of an LED light source allows simultaneous identification of fluorescent tumor of different wavelengths without compromising background illumination. Further development of this technology for clinical use can improve the staging and treatment of pancreatic cancer.

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Immortalizing the complexity of cancer metastasis: Genetic features of lethal metastatic pancreatic cancer obtained from rapid autopsy

Cancer Biology & Therapy ◽

10.4161/cbt.4.5.1663 ◽

2005 ◽

Vol 4 (5) ◽

pp. 548-554 ◽

Cited By ~ 89

Author(s):

Erlinda E. Embuscado ◽

Daniel Laheru ◽

Francesca Ricci ◽

Ki Jung Yun ◽

Sten de Boom Witzel ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Metastasis ◽

Metastatic Pancreatic Cancer ◽

Genetic Features ◽

Rapid Autopsy

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Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.624837 ◽

2021 ◽

Vol 11 ◽

Author(s):

Qing Hua ◽

Tianjiao Li ◽

Yixuan Liu ◽

Xuefang Shen ◽

Xiaoyan Zhu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Poor Prognosis ◽

Culture Media ◽

Disease Free Survival ◽

Mtor Pathway ◽

Gene Set Enrichment Analysis ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a growing cause of cancer-related mortality worldwide. Kallikrein-related peptidase 8 (KLK8) has potential clinical values in many cancers. However, the clinicopathological significances of KLK8 in PDAC remain unknown. We explored the relationship of KLK8 to clinicopathological features of PDAC based on public databases. KLK8 expression was examined in human PDAC tissues. Cell proliferation and apoptosis were evaluated in KLK8-overexpressed human pancreatic cancer cell lines Mia-paca-2 and Panc-1. The related signaling pathways of KLK8 involved in pancreatic cancer progression were analyzed by gene set enrichment analysis (GSEA) and further verified in in vitro studies. We found that KLK8 was up-regulated in tumor tissues in the TCGA-PAAD cohort, and was an independent prognostic factor for both overall survival and disease-free survival of PDAC. KLK8 mRNA and protein expressions were increased in PDAC tissues compared with para-cancerous pancreas. KLK8 overexpression exerted pro-proliferation and anti-apoptotic functions in Mia-paca-2 and Panc-1 cells. GSEA analysis showed that KLK8 was positively associated with PI3K-Akt-mTOR and Notch pathways. KLK8-induced pro-proliferation and anti-apoptotic effects in Mia-paca-2 and Panc-1 cells were attenuated by inhibitors for PI3K, Akt, and mTOR, but not by inhibitor for Notch. Furthermore, overexpression of KLK8 in Mia-paca-2 and Panc-1 cells significantly increased epidermal growth factor (EGF) levels in the culture media. EGF receptor (EGFR) inhibitor could block KLK8-induced activation of PI3K/Akt/mTOR pathway and attenuate pro-proliferation and anti-apoptotic of KLK8 in Mia-paca-2 and Panc-1 cells. In conclusion, KLK8 overexpression exerts pro-proliferation and anti-apoptotic functions in pancreatic cancer cells via EGF signaling-dependent activation of PI3K/Akt/mTOR pathway. Upregulated KLK8 in PDAC predicts poor prognosis and may be a potential therapeutic target for PDAC.

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MicroRNA-296-5p Promotes Cell Invasion and Drug Resistance by Targeting Bcl2-Related Ovarian Killer, Leading to a Poor Prognosis in Pancreatic Cancer

Digestion ◽

10.1159/000503225 ◽

2019 ◽

Vol 101 (6) ◽

pp. 794-806 ◽

Cited By ~ 1

Author(s):

Jun Okazaki ◽

Toshihito Tanahashi ◽

Yasushi Sato ◽

Jinsei Miyoshi ◽

Tadahiko Nakagawa ◽

...

Keyword(s):

Pancreatic Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Cell Invasion ◽

Poor Prognosis ◽

Cancer Cell Lines ◽

Pancreatic Cancer Cells ◽

Cancer Tissues

Background/Aims: Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive invasion, early metastasis, and resistance to chemotherapy, leading to a poor prognosis. To clarify the molecular mechanism of these malignant characteristics, we performed a genome-wide microRNA (miRNA) array analysis utilizing micro-cancer tissues from patients with unresectable PDAC (stage IV), obtained by endoscopic ultrasound-fine needle aspiration (EUS-FNA). Methods: The expression profiles of 2,042 miRNAs were determined using micro-cancer tissues from 13 patients with unresectable PDAC obtained by EUS-FNA. The relationship between individual miRNA levels and overall survival (OS) was analyzed. Possible target genes for miRNAs were bioinformatically analyzed using the online database miRDB. Pancreatic cancer cell lines PANC-1, MIA PaCa-2, and PK-8 were transfected with miRNA mimic or small interfering RNA, and cell invasion, epithelial-mesenchymal transition (EMT), and apoptosis markers were examined. miRNA and mRNA expressions were examined by quantitative polymerase chain reaction. Results: Of 2,042 miRNAs, the 10 that exhibited the lowest correlation coefficient (p ≤ 0.005) between miRNA expression level and OS among the patients were identified. The miRDB and expression analysis in cancer cell lines for the 10 miRNAs identified miR-296-5p and miR-1207-5p as biomarkers predictive of shorter survival (p < 0.0005). Bioinformative target gene analysis and transfection experiments with miRNA mimics showed that Bcl2-related ovarian killer (BOK), a pro-apoptotic gene, is a target for miR296-5p in pancreatic cancer cells; transfection of miR-296-5p mimic into PANC-1, MIA PaCa-2, and PK-8 cells resulted in significant suppression of BOK mRNA and protein expression. These transfectants showed significantly higher invasion capability compared with control cells, and knock down of BOK in pancreatic cancer cells similarly enhanced invasion capability. Transfectants of miR-296-5p mimic also exhibited aberrant expression of EMT markers, including vimentin and N-cadherin. Moreover, these transfectants showed a significantly lower apoptosis rate in response to 5-fluorouracil and gemcitabine with a decrease of BOK expression, suggesting a role of miR-296-5p in drug resistance. Conclusion: These results suggest that miR-296-5p is a useful biomarker for a poor prognosis in patients with PDAC, and that the miR-296-5p/BOK signaling axis plays an important role in cell invasion, drug resistance, and EMT in PDACs.

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Long noncoding RNA GSTM3TV2 upregulates LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance in pancreatic cancer

Journal of Hematology & Oncology ◽

10.1186/s13045-019-0777-7 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 13

Author(s):

Guangbing Xiong ◽

Chang Liu ◽

Gang Yang ◽

Mengyu Feng ◽

Jianwei Xu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Noncoding Rna ◽

Poor Prognosis ◽

Reference Sequence ◽

Gemcitabine Resistance ◽

Cerna Network ◽

Pancreatic Cancer Cells

Abstract Background Chemoresistance is one of the main causes of poor prognosis in pancreatic cancer patients. Understanding the mechanisms implicated in chemoresistance of pancreatic cancer is critical to improving patient outcomes. Recent evidences indicate that the long noncoding RNAs (lncRNAs) are involving in chemoresistance of pancreatic cancer. However, the mechanisms of lncRNAs contribute to resistance in pancreatic cancer and remain largely unknown. The objective of this study is to construct a chemoresistance-related lncRNA-associated competing endogenous RNA (ceRNA) network of pancreatic cancer and identify the key lncRNAs in regulating chemoresistance of the network. Methods Firstly, lncRNA expression profiling of gemcitabine-resistant pancreatic cancer cells was performed to identify lncRNAs related to chemoresistance by microarray analysis. Secondly, with insights into the mechanism of ceRNA, we used a bioinformatics approach to construct a chemoresistance-related lncRNAs-associated ceRNA network. We then identified the topological key lncRNAs in the ceRNA network and demonstrated its function or mechanism in chemoresistance of pancreatic cancer using molecular biological methods. Further studies evaluated its expression to assess its potential association with survival in patients with pancreatic cancer. Results Firstly, we demonstrated that lncRNAs were dysregulated in gemcitabine-resistant pancreatic cancer cells. We then constructed a chemoresistance-related lncRNA-associated ceRNA network and proposed that lncRNA Homo sapiens glutathione S-transferase mu 3, transcript variant 2 and noncoding RNA (GSTM3TV2; NCBI Reference Sequence: NR_024537.1) might act as a key ceRNA to enhance chemoresistance by upregulating L-type amino acid transporter 2 (LAT2) and oxidized low-density lipoprotein receptor 1(OLR1) in pancreatic cancer. Further studies demonstrated that GSTM3TV2, overexpressed in gemcitabine-resistant cells, enhanced the gemcitabine resistance of pancreatic cancer cells in vitro and in vivo. Mechanistically, we identified that GSTM3TV2 upregulated LAT2 and OLR1 by competitively sponging let-7 to promote gemcitabine resistance. In addition, we revealed that the expression levels of GSTM3TV2 were significantly increased in pancreatic cancer tissues and were associated with poor prognosis. Conclusion Our results suggest that GSTM3TV2 is a crucial oncogenic regulator involved in chemoresistance and could be a new therapeutic target or prognostic marker in pancreatic cancer.

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The Pathology and Genetics of Metastatic Pancreatic Cancer

Archives of Pathology & Laboratory Medicine ◽

10.5858/133.3.413 ◽

2009 ◽

Vol 133 (3) ◽

pp. 413-422 ◽

Cited By ~ 21

Author(s):

Shinichi Yachida ◽

Christine A. Iacobuzio-Donahue

Keyword(s):

Pancreatic Cancer ◽

Hedgehog Signaling ◽

Cancer Metastasis ◽

Metastatic Pancreatic Cancer ◽

Critical Determinant ◽

Molecular Features ◽

Pancreatic Cancers ◽

The Poor ◽

Diagnostic Panel ◽

Primary Neoplasms

Abstract Context.—Metastatic disease is the most critical determinant of resectability of pancreatic cancer and accounts for the poor outcome of patients with this disease. Thus, a better understanding of metastatic pancreatic cancer will afford new opportunities for therapeutic intervention. Objective.—To summarize and discuss the current understanding of the clinical and molecular features of metastatic pancreatic cancer. Data Sources.—Published literature on advanced stage pancreatic cancer, pancreatic cancer metastasis, and autopsy findings in patients with pancreatic cancer. Conclusions.—In the clinical setting, it can be difficult to distinguish a metastatic pancreatic carcinoma from primary neoplasms in the liver, lung, or ovary. However, immunolabeling for DPC4 protein as part of a diagnostic panel is useful for making this distinction. Emerging data from a variety of investigators now indicate that overexpression of EphA2, loss of DPC4 and MKK4, and aberrant activation of the Hedgehog signaling pathway are associated with metastatic propensity of pancreatic cancers, providing novel therapeutic targets for the most lethal stage of this disease.

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