Regulatory networks in mechanotransduction reveal key genes in promoting cancer cell stemness and proliferation

Wei Huang, Hui Hu, Qiong Zhang, Xian Wu, Fuxiang Wei, Fang Yang, Lu Gan, Ning Wang, Xiangliang Yang, An Yuan Guo

Research output: Contribution to journalArticlepeer-review


Tumor-repopulating cells (TRCs) are cancer stem cell (CSC)-like cells with highly tumorigenic and self-renewing abilities, which were selected from tumor cells in soft three-dimensional (3D) fibrin gels with unidentified mechanisms. Here we evaluated the transcriptome alteration during TRCs generation in 3D culture and revealed that a variety of molecules related with integrin/membrane and stemness were continuously altered by mechanical environment. Some key regulators such as MYC/STAT3/hsa-miR-199a-5p, were changed in the TRCs generation. They regulated membrane genes and the downstream mechanotransduction pathways such as Hippo/WNT/TGF-β/PI3K-AKT pathways, thus further affecting the expression of downstream cancer-related genes. By integrating networks for membrane proteins, the WNT pathway and cancer-related genes, we identified key molecules in the selection of TRCs, such as ATF4, SLC3A2, CCT3, and hsa-miR-199a-5p. Silencing ATF4 or CCT3 inhibited the selection and growth of TRCs whereas reduction of SLC3A2 or hsa-miR-199a-5p promoted TRCs growth. Further studies showed that CCT3 promoted cell proliferation and stemness in vitro, while its suppression inhibited TRCs-induced tumor formation. We also contemplated CCT3 as a stemness-related gene. Our findings provide insights in the mechanism of TRCs selection through transcriptome analysis.

Original languageEnglish (US)
Pages (from-to)6818-6834
Number of pages17
Issue number42
StatePublished - Oct 17 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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