Epithelial-mesenchymal transition (EMT) is a critical event that occurs during the invasion and metastatic spread of cancer cells. Here, we conceive a dual mechanism of Par-4-mediated inhibition of EMT and induction of MET in metastatic pancreatic cancer cells. First, we demonstrate that 1,1'-β-D-glucopyranosyl-3,3'-bis(5-bromoindolyl)-octyl methane (NGD16), an N-glycosylated derivative of medicinally important phytochemical 3,3'-diindolylmethane (DIM) abrogates EMT by inducing pro-apoptotic protein Par-4. Induction of Par-4 (by NGD16 or ectopic overexpression) strongly impedes invasion with inhibition of major mesenchymal markers viz. Vimentin and Twist-1 epithelial marker- E-cadherin. Further, NGD16 triggers MET phenotypes in pancreatic cancer cells by augmenting ALK2/Smad4 signaling in a Par-4-dependent manner. Conversely, siRNA-mediated silencing of endogenous Par-4 unveil reversal of MET with diminished E-cadherin expression and invasive phenotypes. Additionally, we demonstrate that intact Smad4 is essential for Par-4-mediated maintenance of E-cadherin level in MET induced cells. Notably, we imply that Par-4 induction regulates E-cadherin levels in the pancreatic cancer cells via modulating Twist-1 promoter activity. Finally, in vivo studies with syngenic mouse metastatic pancreatic cancer model reveal that NGD16 strongly suppresses metastatic burden, ascites formation, and prolongs the overall survival of animals effectively.
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http://dx.doi.org/10.1002/mc.22828 | DOI Listing |
Clin Epigenetics
December 2024
Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
Background: Pancreatic adenocarcinoma (PDAC) exhibits a complex microenvironment with diverse cell populations influencing patient prognosis. Single-cell RNA sequencing (scRNA-seq) was used to identify prognosis-related cell types, and DNA methylation (DNAm)-based models were developed to predict outcomes based on their cellular characteristics.
Methods: We integrated scRNA-seq, bulk data, and clinical information to identify key cell populations associated with prognosis.
BMC Surg
December 2024
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Background: Abdominal fluid collection (AFC) is one of the most common complications after pancreatic surgery, yet there are few recommendations on how to manage it. Most cases of AFC only require observation, while others may require more invasive techniques. Unfortunately, there are no drugs that effectively promote the absorption of AFCs.
View Article and Find Full Text PDFBMC Surg
December 2024
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Background: The introduction of enhanced recovery programmes (ERP) in pancreatic surgery has significantly improved clinical outcomes by decreasing the length of hospital stay, cost and complications without increasing readmissions and reoperations. To complement evidence on these outcomes, there is a need to explore patients' perspectives of a structured ERP. Therefore, this study aimed to explore the health-related quality of life (HRQoL) of patients before and after implementing ERP in pancreaticoduodenectomy ad modum Whipple (PD) at a regional surgical centre.
View Article and Find Full Text PDFPancreatology
December 2024
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. Electronic address:
Background: Multiple management guidelines for intraductal papillary mucinous neoplasms (IPMNs) have been published to improve risk stratification and resource utilization. This study aims to evaluate trends in endoscopic ultrasound (EUS) use and agreement between cross-sectional imaging and EUS for specific pancreas cystic lesion (PCL) features.
Methods: This retrospective cohort study included consecutive adults undergoing EUS for suspected IPMN detected with cross-sectional imaging (CT/MRCP) between 2013 and 2015 (Cohort 1) and 2018-2020 (Cohort 2).
Surgery
December 2024
Department of Surgery, Osaka International Cancer Institute, Osaka, Japan.
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