Abstract
The Hippo signaling pathway plays a crucial role in regulating tissue homeostasis, organ size, tumorigenesis and cancer chemoresistance when deregulated. Physiologically, the Hippo core kinase cassette that consists of mamma-lian STE20-like protein kinase 1/2 (MST1/2), and large tumour suppressor 1/2 (LATS1/2), together with the adaptor proteins Salvador homologue 1 (SAV1) and MOB kinase activator 1 (MOB1), tightly restricts the activities of homologous oncoproteins Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) to low levels. However, how the Hippo kinase cassette core components are simultaneously inhibited, to exhibit constitutively inactivated Hippo signaling and activated YAP/TAZ in cancer remains puzzling. Herein, we reported that miR-181c directly repressed MST1, LATS2, MOB1 and SAV1 expression in human pancreatic cancer cells. Overexpression of miR-181c induced hyperactivation of the YAP/TAZ and enhanced expression of the Hippo signaling downstream genes CTGF, BIRC5 and BLC2L1, leading to pancreatic cancer cell survival and chemoresistance in vitro and in vivo. Importantly, high miR-181c levels were significantly correlated with Hippo signaling inactivation in pancreatic cancer samples, and predicted a poor patient overall survival. These findings provide a novel mechanism for Hippo signaling inactivation in cancer, indicating not only a potentially pivotal role for miR-181c in the progression of pancreatic cancer, but also may represent a new therapeutic target and prognostic marker.
Keywords:
Hippo signaling; chemoresistance; miR-181c; pancreatic cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antineoplastic Agents / pharmacology*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Survival
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / genetics
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Gene Expression Regulation, Neoplastic
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Hippo Signaling Pathway
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Kaplan-Meier Estimate
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Mice, Inbred BALB C
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Mice, Nude
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / enzymology
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / pathology
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Signal Transduction / drug effects*
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Time Factors
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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Transfection
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Tumor Burden / drug effects
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Up-Regulation
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Xenograft Model Antitumor Assays
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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Cell Cycle Proteins
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Intracellular Signaling Peptides and Proteins
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MIRN-181 microRNA, human
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MicroRNAs
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Phosphoproteins
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SAV1 protein, human
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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Tumor Suppressor Proteins
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WWTR1 protein, human
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YAP-Signaling Proteins
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YAP1 protein, human
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LATS2 protein, human
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STK4 protein, human
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Protein Serine-Threonine Kinases