Hippo Signaling Mediates Proliferation, Invasiveness, and Metastatic Potential of Clear Cell Renal Cell Carcinoma

Abstract

Recent work has identified dysfunctional Hippo signaling to be involved in maintenance and progression of various human cancers, although data on clear cell renal cell carcinoma (ccRCC) have been limited. Here, we provide evidence implicating aberrant Hippo signaling in ccRCC proliferation, invasiveness, and metastatic potential. Nuclear overexpression of the Hippo target Yes-associated protein (YAP) was found in a subset of patients with ccRCC. Immunostaining was particularly prominent at the tumor margins and highlighted neoplastic cells invading the tumor-adjacent stroma. Short hairpin RNA-mediated knockdown of YAP significantly inhibited proliferation, migration, and anchorage-independent growth of ccRCC cells in soft agar and led to significantly reduced murine xenograft growth. Microarray analysis of YAP knockdown versus mock-transduced ccRCC cells revealed down-regulation of endothelin 1, endothelin 2, cysteine-rich, angiogenic inducer, 61 (CYR61), and c-Myc in ccRCC cells as well as up-regulation of the cell adhesion molecule cadherin 6. Signaling pathway impact analysis revealed activation of the p53 signaling and cell cycle pathways as well as inhibition of mitogen-activated protein kinase signaling on YAP down-regulation. Our data suggest CYR61 and c-Myc as well as signaling through the endothelin axis as bona fide downstream effectors of YAP and establish aberrant Hippo signaling as a potential therapeutic target in ccRCC.

Long noncoding RNA TUG1 promotes cell proliferation and migration of renal cell carcinoma via regulation of YAP

“…34 Although mutations of the Hippo pathway components were rarely observed in tumors, aberrant expression of YAP was frequently detected in cancers of various types. 36 Altered expressions of angiomotin and LATS have been discovered to contribute to the loss of YAP control in RCC. Knockdown of YAP inhibited cell growth, migration, anchor-independent growth of RCC cells in vitro, and suppressed tumor formation in vivo.…”

Hippo signaling in the kidney: the good and the bad

“…Aberrant Hippo pathway signaling resulting in hyperactive YAP function has been detected in various human cancers, including those affecting the kidney. Nuclear overexpression of YAP has been detected in a subset of patients with ccRCC (56). Yap silencing also reduces proliferation, migration, and anchorage-independent growth of ccRCC cells (56).…”

“…Nuclear overexpression of YAP has been detected in a subset of patients with ccRCC (56). Yap silencing also reduces proliferation, migration, and anchorage-independent growth of ccRCC cells (56). Yap mRNA and protein expression levels are also increased in ccRCC tissue and cell lines.…”

Kidney-specific knockout ofSav1in the mouse promotes hyperproliferation of renal tubular epithelium through suppression of the Hippo pathway

“…Furthermore, we identified Salvador homologue 1 ( SAV1 ) as a candidate gene responsible for 14q loss . SAV1 is one of the core components of the Hippo pathway, which mainly functions in the control of organ size and tumourigenesis through regulation of its downstream target gene, Yes‐associated protein 1 ( YAP1 ) . We have shown that expression of SAV1 correlated well with both the status of 14q loss and nuclear grading in clinical cases, and inhibits the proliferation of RCC cells .…”