Differential expression of tumor-associated genes and altered gut microbiome with decreased Akkermansia muciniphila confer a tumor-preventive microenvironment in intestinal epithelial Pten-deficient mice

Biochim Biophys Acta Mol Basis Dis. 2018 Dec;1864(12):3746-3758. doi: 10.1016/j.bbadis.2018.10.006. Epub 2018 Oct 4.

Abstract

Phosphatase and tensin homolog (Pten) antagonizes PI3K-Akt signaling; therefore, Pten impairment causes tumorigenesis. However, the correlation between Pten deficiency and colon cancer has remained elusive due to numerous opposite observations. To study this correlation, we examined whether Pten deficiency in intestinal epithelial cells (IECs) induces tumorigenesis. With mucosal biopsies of human colon cancer and normal colon, Pten mRNA was evaluated by quantitative PCR. Using IEC-specific Pten knockout mice (PtenΔIEC/ΔIEC), we examined the mitotic activity of IECs; and PtenΔIEC/ΔIEC; Apcmin/+ mice were generated by combining PtenΔIEC/ΔIEC with Apcmin/+ mice. Tumor-associated gene was evaluated by micro-array analysis. Fecal microbiome was analyzed through 16S rRNA gene sequencing. We found that Pten mRNA level was reduced in human colon cancer relative to normal tissues. Augmented chromatids, increased Ki-67 and PCNA expression, and enhanced Akt activation were identified in IECs of PtenΔIEC/ΔIEC mice compared to Pten+/+ littermate. Combining PtenΔIEC/ΔIEC with Apcmin/+ condition caused rapid and aggressive intestinal tumorigenesis. However, PtenΔIEC/ΔIEC mice did not develop any tumors. While maintaining the tumor-driving potential, these data indicated that IEC-Pten deficiency alone did not induce tumorigenesis in mice. Furthermore, the expression of tumor-promoting and tumor-suppressing genes was decreased and increased, respectively, in the intestine of PtenΔIEC/ΔIEC mice compared to controls. The abundance of Akkermansia muciniphila, capable of inducing chronic intestinal inflammation, was diminished in PtenΔIEC/ΔIEC mice compared to controls. These findings suggested that altered tumor-associated gene expression and changed gut microbiota shape a tumor-preventive microenvironment to counteract the tumor-driving potential, leading to the tumor prevention in PtenΔIEC/ΔIEC mice.

Keywords: Microbiome; Pten; Toll-like receptor; Tumor microenvironment; Tumor prevention.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Carcinogenesis / genetics*
  • Carcinogenesis / pathology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Gastrointestinal Microbiome*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intestinal Neoplasms / genetics*
  • Intestinal Neoplasms / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • PTEN Phosphohydrolase / genetics*
  • Verrucomicrobia / growth & development
  • Verrucomicrobia / isolation & purification*

Substances

  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Pten protein, mouse