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Macrophage-targeted therapy offers new options for intractable pancreatic ductal adenocarcinoma (PDAC), which has a low 5-year survival rate. However, the factors regulating the biological function and phenotype of macrophages in PDAC are incompletely understood. Here, we found that CD51 was positively associated with the poor prognosis of PDAC patients and was highly expressed on macrophages but not on pancreatic cancer cells. Subsequently, we found that CD51 was a marker of macrophages, which promoted the stemness of pancreatic cancer cells. Furthermore, knockdown of CD51 in macrophages drove macrophages toward an M1-like phenotype. Mechanistically, macrophage-expressed CD51 contributed to the acquisition of stemness traits of pancreatic cancer cells by regulating the TGF-β1/smad2/3 pathway. Our data demonstrate the central role played by macrophage-expressed CD51 in the acquisition of stemness traits of pancreatic cancer cells through the paracrine induction of TGF-β1. We first show the connection between the CD51/TGF-β1/smad2/3 axis and PDAC cancer stem cell properties and then indicate that CD51-targeted therapy is a new therapeutic modality for PDAC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Our previous study demonstrated that long non-coding RNA (lncRNA) HOTTIP was maximally expressed in PDAC, and promoted cancer cell progression and epithelial to mesenchymal transition (EMT). Numerous studies indicated that lncRNAs or EMT supported cancer stem cells. However, the role of HOTTIP in pancreatic cancer stem cells (PCSCs) remains unclear. Here, we evaluated the role and mechanism of HOTTIP in PCSCs. First, we analyzed the relationship between HOTTIP expression and overall or disease-free survival in 90 patients with PDAC after radical resection. Patients with higher HOTTIP expression had shorter disease-free survival and overall survival than those with lower expression. Expression of HOTTIP and other lncRNAs was detected in PCSCs and non-PCSCs by laser capture microdissection (LCM). HOTTIP was highly expressed in PCSCs. In addition, in vitro assays showed that HOTTIP alterations affected stemness, including sphericity, tumorigenesis, and stem factors (LIN28, NANOG, OCT4, and SOX2) and markers (ALDH1, CD44, and CD133). Mechanistically, HOTTIP mediated HOXA9 to enhance the Wnt/β-catenin pathway by binding to WDR5 in PCSCs. In vivo results showed that HOTTIP or HOXA9 alterations influenced stemness. Our results indicate that the HOTTIP/WDR5/HOXA9/Wnt axis contributes to PCSC stemness and is a potential therapeutic target for PDAC., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Long non-coding RNAs (lncRNAs) are important regulators in pathological processes, yet their potential roles in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we found that a novel lncRNA, LOC389641, was upregulated in PDAC tissues and cell lines. The expression of LOC389641 was significantly correlated with staging, lymph node metastasis and overall survival. Knockdown of LOC389641 impaired cell proliferation and invasion and induced cell apoptosis in vitro, whereas overexpression of LOC389641 had the opposite effect. The growth promoting effect of LOC389641 was also demonstrated in vivo. Further, a significant negative correlation was observed between E-cadherin levels and LOC389641 levels in vivo. Knockdown of LOC389641 upregulated E-cadherin expression, but knockdown of E-cadherin had a limited influence on LOC389641. Importantly, after E-cadherin was inhibited, the enhancement of LOC389641 on cell invasion was hindered. Moreover, the expression of LOC389641 was closely associated with its genomic neighboring gene TNFRSF10A. Lastly, knockdown experiments showed that TNFRSF10A might be a connection between LOC389641and E-cadherin. We conclude that LOC389641 promotes PDAC progression and increases cell invasion by regulating E-cadherin with the possible involvement of TNFRSF10A., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)