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Copyright of BBA - Gene Regulatory Mechanisms is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The mucin MUC4 and its membrane partner the ErbB2 oncogenic receptor are potential interacting partners in human pancreatic tumour development. However, the way they function is still largely unknown. In this work, we aimed to identify the cellular mechanisms and the intracellular signalling pathways under the control of both ErbB2 and MUC4 in a human pancreatic adenocarcinomatous cell line. Using co-immunoprecipitation and GST pull-down, we show that MUC4 and ErbB2 interact in the human pancreatic adenocarcinomatous cell line CAPAN-2 via the EGF domains of MUC4. Stable cell clones were generated in which either MUC4 or ErbB2 were knocked down (KD) by a shRNA approach. Biological properties of these cells were then studied in vitro and in vivo. Our results show that ErbB2-KD cells are more apoptotic and less proliferative (decreased cyclin D1 and increased p27kip1 expression) while migration and invasive properties were not altered. MUC4-KD clones were less proliferative with decreased cyclin D1 expression, G1 cell cycle arrest and altered ErbB2/ ErbB3 expression. Their migration properties were reduced whereas invasive properties were increased. Importantly, inhibition of ErbB2 and MUC4 expression did not impair the same signalling pathways (inhibition of MUC4 expression affected the JNK pathway whereas that of ErbB2 altered the MAPK pathway). Finally, ErbB2-KD and MUC4-KD cells showed impaired tumour growth in vivo. Our results show that ErbB2 and MUC4, which interact physically, activate different intracellular signalling pathways to regulate biological properties of CAPAN-2 pancreatic cancer cells. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is characterized by an often dramatic outcome (five year survival < 5%) related to a late diagnosis and a lack of efficient therapy. Therefore, clinicians desperately need new biomarkers and new therapeutic tools to develop new efficient therapies. Mucins belong to an ever increasing family of O-glycoproteins. Secreted mucins are the main component of mucus protecting the epithelia whereas membrane-bound mucins are thought to play important biological roles in cell-cell and cell-matrix interactions, in cell signaling and in modulating biological properties of cancer cells. In this review, we will focus on the altered expression pattern of mucins in pancreatic cancer, from the early neoplastic lesion Pancreatic Intraepithelial Neoplasia (PanIN) to invasive pancreatic carcinomas, and the molecular mechanisms (including genetic and epigenetic regulation) and signaling pathways known to control their expression. Moreover, we will discuss the recent advances about the biology of both secreted and membrane-bound mucins and their key roles in pancreatic carcinogenesis and resistance to therapy. Finally, we will discuss exciting opportunities that mucins offer as potential therapeutic targets in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: A feature of pancreatic cancer (PC) is the frequent overexpression of tyrosine kinase membrane receptor HER2 along with its membrane partner the MUC4 oncomucin in the early stages of the pancreatic carcinogenesis. However, therapeutic approaches targeting HER2 in PC are not efficient. MUC4 could indeed represent an alternative therapeutic strategy to target HER2 signaling pathway, but this approach needs to characterize MUC4/HER2 interaction at the molecular level. In this study, we successfully showed the impact of the EGF domains of MUC4 on HER2 binding affinity and demonstrated their "growth factor-like" biological activities in PC cells. Moreover, homology models of the MUC4EGF/HER2 complexes allowed identification of binding hotspots mediating binding affinity with HER2 and PC cell proliferation. These results allow a better understanding of the mechanisms involved in the MUC4/HER2 complex formation and may lead to the design of potential MUC4/HER2 inhibitors. The HER2 receptor and its MUC4 mucin partner form an oncogenic complex via an extracellular region of MUC4 encompassing three EGF domains that promotes tumor progression of pancreatic cancer (PC) cells. However, the molecular mechanism of interaction remains poorly understood. Herein, we decipher at the molecular level the role and impact of the MUC4EGF domains in the mediation of the binding affinities with HER2 and the PC cell tumorigenicity. We used an integrative approach combining in vitro bioinformatic, biophysical, biochemical, and biological approaches, as well as an in vivo study on a xenograft model of PC. In this study, we specified the binding mode of MUC4EGF domains with HER2 and demonstrate their "growth factor-like" biological activities in PC cells leading to stimulation of several signaling proteins (mTOR pathway, Akt, and β-catenin) contributing to PC progression. Molecular dynamics simulations of the MUC4EGF/HER2 complexes led to 3D homology models and identification of binding hotspots mediating binding affinity with HER2 and PC cell proliferation. These results will pave the way to the design of potential MUC4/HER2 inhibitors targeting the EGF domains of MUC4. This strategy will represent a new efficient alternative to treat cancers associated with MUC4/HER2 overexpression and HER2-targeted therapy failure as a new adapted treatment to patients. [ABSTRACT FROM AUTHOR]