Inhibition of primary cilia-hedgehog signaling axis triggers autophagic cell death and suppresses malignant progression of VHL wild-type ccRCC

Author:

Huang Yan1,Tian Shuo1,Du SongliangORCID,Wang Chenfeng1,zhang yu2,Wang Hanfeng1,fan yang2,gao yu2,Gu Liangyou3,Huang Qingbo2ORCID,Wang Baojun1,ma xin2,Zhang Xu1

Affiliation:

1. The Third Medical Centre of Chinese PLA General Hospital

2. Chinese PLA General Hospital

3. Chinese People's Liberation Army (PLA) General Hospital/ PLA Medical School

Abstract

Abstract

Primary cilia are present on renal tubules and are implicated to play pivotal role in transducing signals during development; however, the oncogenic role of cilia in clear cell renal cell carcinoma (ccRCC) has not been examined. Here we show that VHL wild-type ccRCC cell lines have high incidence of primary cilia, and high frequency of primary cilia is positively correlated with VHL expression and poor prognosis. Besides, depletion Kif3a or Ift88, genes required for ciliogenesis, significantly inhibited tumor proliferation and metastasis in vitro and in vivo. Further analysis found that mutations of key genes in hedgehog signaling are enriched in VHL wild ccRCC, its downstream signaling activation depends on ciliogenesis. Moreover, depletion of primary cilia or suppression of hedgehog pathway activation with inhibitor induced robust autophagic cell death. Collectively, our findings revealed that primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of VHL wild-type ccRCC progression. Targeting primary cilia-hedgehog pathway may represent an effective therapeutic strategy for VHL wild-type ccRCC.

Publisher

Research Square Platform LLC

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