Expression of Core Hippo Pathway Proteins in Cervical Cancer and Their Association with Clinicopathologic Parameters

Abstract

Background: The Hippo signaling pathway, a highly conserved regulatory cascade, regulates tissue homeostasis, organ size, and tumor suppression. Dysregulation of this pathway contributes to oncogenesis in various human malignancies; however, its clinicopathologic relevance in cervical cancer has not been completely elucidated. Therefore, this study aimed to investigate the expression patterns of key Hippo pathway proteins and analyze their associations with tumor behavior and clinicopathologic features in cervical carcinoma. Materials and Methods: Ninety-nine cervical cancer specimens obtained from hysterectomies performed at Gyeongsang National University Hospital (2012-2019) were retrospectively analyzed. Immunohistochemical staining for Yes-associated protein (YAP), phosphorylated YAP (p-YAP), mammalian sterile-20-like kinase-1 (MST1), and large tumor suppressor kinase-1 (LATS1) was performed on tissue microarrays. Chi-square or Fisher's exact tests and logistic regression were employed for assessing associations between marker expression and clinicopathologic variables. Functional validation was conducted via small interfering RNA-mediated YAP knockdown in Caski cervical cancer cells, with reverse transcription-polymerase chain reaction, Western blotting, and wound-healing assays assessing YAP suppression and cell migration. Results: YAP and p-YAP were expressed in 71.8% and 62.6% of tumors, respectively; MST1 in 82.8%; and LATS1 in 22.2%. YAP and p-YAP overexpression was correlated with larger tumor size (p = 0.013 and p = 0.011) and higher International Federation of Gynecology and Obstetrics stage (p = 0.007 and p < 0.001). YAP and p-YAP expression was positively correlated (odds ratio, 4.34; 95% confidence interval, 1.70-11.61). MST1 or LATS1 expression demonstrated no significant associations. In vitro, YAP silencing decreased mRNA and protein expression levels and significantly impaired cell migration, supporting its role in tumor aggressiveness. Conclusions: YAP and p-YAP overexpression are associated with advanced stage and larger tumor size in cervical cancer, indicating Hippo pathway dysregulation. YAP functional suppression attenuated migratory capacity, highlighting YAP as a promising prognostic biomarker and therapeutic target.