Hippo-YAP1 Is a Prognosis Marker and Potentially Targetable Pathway in Advanced Gallbladder Cancer.

Patricia García,Alfredo Sagredo,Nicole Elgueta,Felipe Suárez,Bruno Nervi,Isabel Romero-Calvo,Jaime A Espinoza,Helga Weber,Javiera Obreque,Vanessa Rivera,Carolina Bizama,Sabrina Muñiz,Lorena Rosa,Sergio Vargas,Juan C Roa,Eduardo Viñuela,Gloria Aguayo,Pamela Leal

doi:10.3390/cancers12040778

Abstract

Gallbladder cancer is an aggressive disease with late diagnosis and no efficacious treatment. The Hippo-Yes-associated protein 1 (YAP1) signaling pathway has emerged as a target for the development of new therapeutic interventions in cancers. However, the role of the Hippo-targeted therapy has not been addressed in advanced gallbladder cancer (GBC). This study aimed to evaluate the expression of the major Hippo pathway components mammalian Ste20-like protein kinase 1 (MST1), YAP1 and transcriptional coactivator with PDZ-binding motif (TAZ) and examined the effects of Verteporfin (VP), a small molecular inhibitor of YAP1-TEA domain transcription factor (TEAD) protein interaction, in metastatic GBC cell lines and patient-derived organoids (PDOs). Immunohistochemical analysis revealed that advanced GBC patients had high nuclear expression of YAP1. High nuclear expression of YAP1 was associated with poor survival in GBC patients with subserosal invasion (pT2). Additionally, advanced GBC cases showed reduced expression of MST1 compared to chronic cholecystitis. Both VP treatment and YAP1 siRNA inhibited the migration ability in GBC cell lines. Interestingly, gemcitabine resistant PDOs with high nuclear expression of YAP1 were sensitive to VP treatment. Taken together, our results suggest that key components of the Hippo-YAP1 signaling pathway are dysregulated in advanced gallbladder cancer and reveal that the inhibition YAP1 may be a candidate for targeted therapy.

Highlights

The gallbladder cancer (GBC) is the seventh most common gastrointestinal cancer worldwide, with an incidence of 2.3/100,000 and mortality rate of 1.7/100,000 [1]
The expression levels of Hippo pathway core components including STK3/STK4 (MST1/2), LATS1/2, SAV1, MOB1A/1B, Yes-associated protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ) were characterized by RT-qPCR
We found that transcript expression of SAV1 was downregulated by 1.65-fold (p = 0.003), LATS2 by 1.95-fold (p = 0.010) and YAP1 by 1.4-fold (p = 0.007) in tumor samples compared with CC samples (Figure S1)

Summary

Introduction

The gallbladder cancer (GBC) is the seventh most common gastrointestinal cancer worldwide, with an incidence of 2.3/100,000 and mortality rate of 1.7/100,000 [1]. Advanced or metastatic GBC is associated with late diagnosis, unsatisfactory treatment and poor prognosis. The Hippo-Yes-associated protein 1 (YAP1) signaling pathway is dysregulated in many different cancers and has recently emerged as a master regulator that playing a central role in tumorigenesis, regulation of apoptosis, acquisition of tumor stem cell phenotype, drug resistance and metastatic potential [2]. Li et al, reported for the first time that nuclear YAP1 is expressed in most GBC cases and that high nuclear YAP1 expression was associated with advanced tumor stage and worse patient survival. Knockdown of YAP1 by shRNA in GBC-SD and OCUG-1 gallbladder cells significantly inhibited cell proliferation and invasion in vitro and inhibited cancer cell growth in vivo [6]

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