Wnt7a is a novel inducer of β-catenin-independent tumor-suppressive cellular senescence in lung cancer

Oncogene
Rama Kamesh BikkavilliRobert A Winn

Abstract

Cellular senescence is an initial barrier for carcinogenesis. However, the signaling mechanisms that trigger cellular senescence are incompletely understood, particularly in vivo. Here we identify Wnt7a as a novel upstream inducer of cellular senescence. In two different mouse strains (C57Bl/6J and FVB/NJ), we show that the loss of Wnt7a is a major contributing factor for increased lung tumorigenesis owing to reduced cellular senescence, and not reduced apoptosis, or autophagy. Wnt7a-null mice under de novo conditions and in both the strains display E-cadherin-to-N-cadherin switch, reduced expression of cellular senescence markers and reduced expression of senescence-associated secretory phenotype, indicating a genetic predisposition of these mice to increased carcinogen-induced lung tumorigenesis. Interestingly, Wnt7a induced an alternate senescence pathway, which was independent of β-catenin, and distinct from that of classical oncogene-induced senescence mediated by the well-known p16(INK4a) and p19(ARF) pathways. Mechanistically, Wnt7a induced cellular senescence via inactivation of S-phase kinase-associated protein 2, an important alternate regulator of cellular senescence. Additionally, we identified Iloprost, a prostacyc...Continue Reading

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Citations

Jun 10, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Yichong WangMing Liu
Dec 23, 2016·Annals of the American Thoracic Society·Mareike LehmannMelanie Königshoff
Jul 5, 2019·Journal of Cellular Biochemistry·Lihui LanChenghai Zhao
Sep 28, 2018·Neuromolecular Medicine·Marton TompaBernadette Kalman
Oct 31, 2017·Frontiers in Cellular Neuroscience·Matthew McCordSadhana Jackson
Feb 21, 2019·American Journal of Physiology. Lung Cellular and Molecular Physiology·Pavan ParikhY S Prakash
May 22, 2020·Anti-cancer Agents in Medicinal Chemistry·Monserrat Alvarez-ZavalaLuis F Jave-Suarez
Aug 31, 2021·Frontiers in Cell and Developmental Biology·Jing YangXing Zhang

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Methods Mentioned

BETA
RNA-seq
PCR
antibody
Transgenic
biopsies
Transfection
confocal microscopy
flow cytometry
PCRs

Software Mentioned

ImageJ
Cytoscape
ImageScope
Aperio Scanscope CS
Cufflinks

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