4.7 Article

NHERF1 inhibits beta-catenin-mediated proliferation of cervical cancer cells through suppression of alpha-actinin-4 expression

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CELL DEATH & DISEASE
卷 9, 期 -, 页码 -

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NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-018-0711-x

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资金

  1. National Natural Science Foundation of the People's Republic of China [81772707, 81572333, 81302373, 81272887]
  2. Scientific Research Key Program of Beijing Municipal Commission of Education [KZ201710025015]
  3. Scientific Research Common Program of Beijing Municipal Commission of Education [KM201410025001]
  4. Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan [IDHT20170516]
  5. BaiQianWan Talents Program
  6. Beijing Natural Science Foundation Program

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Cervical cancer is one of the most lethal types of cancer in female. Aberrant activation of Wnt/beta-catenin signaling pathway has been found to be involved in cervical cancer development and progression, whereas the underlying molecular mechanisms remain poorly understood. The present study showed that NHERF1 was a novel gene associated with both cell proliferation and Wnt signaling pathway in cervical cancer by analysis of differential gene expression and gene cluster for the cervical cancer specimens from GEO data sets. It was further demonstrated in cellular study that NHERF1 inhibition of cervical cancer cell proliferation through Wnt/beta-catenin signaling was dependent on alpha-actinin-4 (ACTN4) expression. A negative association between NHERF1 expression and levels of ACTN4 and beta-catenin was found in mouse xenograft model and cervical cancer specimens. Low levels of NHERF1 in cervical cancer specimens were found to associate with activation of cell proliferation and Wnt/beta-catenin signaling by gene set enrichment analysis, and also were an independent predictive factor for worse prognosis of cervical cancer patients by Cox regression analysis. These findings demonstrate that NHERF1 inhibits Wnt signaling-mediated proliferation of cervical cancer via suppression of ACTN4, and NHERF1 downregulation may contribute to the progression of cervical cancer. These findings may also shed some lights for understanding the underlying mechanisms of cisplatin resistance and worse prognosis of HPV-inactive cervical cancer patients.

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