Roles of Pin1 as a Key Molecule for EMT Induction by Activation of STAT3 and NF-κB in Human Gallbladder Cancer

Journal Article · Fri Mar 15 04:00:00 EDT 2019 · Annals of Surgical Oncology (Online)

DOI:https://doi.org/10.1245/S10434-018-07132-7· OSTI ID:22927875

Nakada, Shinichiro; Kuboki, Satoshi; Nojima, Hiroyuki; Yoshitomi, Hideyuki; Furukawa, Katsunori; Takayashiki, Tsukasa; Takano, Shigetsugu; Miyazaki, Masaru; Ohtsuka, Masayuki ^[1]

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1. Chiba University, Department of General Surgery, Graduate School of Medicine (Japan)

Background: Despite developments in multidisciplinary treatment, the prognosis for advanced gallbladder cancer (GBC) still is poor because of its rapid progression. Epithelial–mesenchymal transition (EMT) plays a central role in promoting tumor invasion and metastasis in malignancies thorough signal transducer and activator of transcription-3 (STAT3) and nuclear factor κB (NF-κB) activation. Whereas Pin1 mediates STAT3 and NF-κB activation, the involvement of Pin1 in GBC progression is unclear. Methods: Factors regulating Pin1-related STAT3 and NF-κB activation were evaluated using surgical specimens collected from 76 GBC patients, GBC cells, and orthotopic GBC xenograft mice. Results: In the patients with GBC, high Pin1 expression in GBC was associated with aggressive tumor invasion and increased tumor metastasis, and was an independent factor for a poor prognosis. Pin1 expression was correlated with phosphorylation of STAT3(Ser727) and NF-κB-p65(Ser276), thereby activating STAT3 and NF-κB in GBC. Pin1-mediated STAT3 and NF-κB activation induced EMT in GBC. When Pin1 knockdown was performed in GBC cells, the phosphorylation of STAT3(Ser727) and NF-κB-p65(Ser276) was inhibited, and STAT3 and NF-κB activation was suppressed. Inactivation of STAT3 and NF-κB in Pin1-depleted cells decreased snail and zeb-2 expression, thereby reducing the rate of mesenchymal-like cells, suggesting that EMT was inhibited in GBC cells. PiB, a Pin1-specific inhibitor, inhibited EMT and reduced tumor cell invasion by inactivating STAT3 and NF-κB in vitro. Moreover, PiB treatment inhibited lymph node metastasis and intrahepatic metastasis in orthotopic GBC xenograft tumor in vivo. Conclusions: Pin1 accelerates GBC invasion and metastasis by activating STAT3 and NF-κB. Therefore, Pin1 inhibition by PiB is an excellent therapy for GBC by safely inhibiting its metastasis.

• OSTI ID: 22927875
• Journal Information: Annals of Surgical Oncology (Online), Journal Name: Annals of Surgical Oncology (Online) Journal Issue: 3 Vol. 26; ISSN 1534-4681
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BILIARY TRACT
INACTIVATION
LYMPH NODES
METASTASES
MICE
NEOPLASMS
PHOSPHORYLATION
THERAPY
TUMOR CELLS