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.
Highlights
Pancreatic cancer is one of the most lethal gastrointestinal tract malignancies and the seventh most common cause of cancer-related death worldwide [1]
Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are largely restricted to a low level of activities by the Hippo kinase cascade consisting of MST1, LATS2, MOB kinase activator 1 (MOB1) and Salvador homologue 1 (SAV1), which sequentially phosphorylate YAP/TAZ to restrict in cytoplasm and degradate [10, 25, 26]
Mounting evidence has indicated that YAP and TAZ are constitutively activated in a wide range of tumor types and are involved in tumor progression by promoting uncontrolled cell proliferation, resistance to apoptosis and even distant metastasis [7, 38]
Summary
Pancreatic cancer is one of the most lethal gastrointestinal tract malignancies and the seventh most common cause of cancer-related death worldwide [1]. Despite chemotherapy involving multiple drugs, including gemcitabine, the median survival time of patients with advanced pancreatic cancer over the past decades has been only about six months, mostly because of an almost complete resistance against chemotherapies [3, 4]. It would be of great clinical value to further understand the molecular mechanisms underlying pancreatic cancer chemoresistance and to identify effective early markers for the diagnosis and prognosis of the disease as well as novel therapeutic targets
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