Heterozygous disruption of the PTEN promotes intestinal neoplasia in APCmin/+ mouse: roles of osteopontin.
The persistent activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is oncogenic and involved in colorectal neoplasia. Mutations of both regulatory subunit and catalytic subunit of PI3K have been demonstrated in colon cancers. In the present study, we show that heterozygous disruption of the phosphatase and tensin homolog (PTEN) tumor suppressor gene promoted tumor progression in APC(min/+) mice. Number and size of intestinal tumors were significantly increased in mice bearing both adenomatous polyposis coli (APC) and PTEN mutations. While APC(min/+)PTEN(+/+) mice developed adenomas, invasive carcinomas developed in APC(min/+)PTEN(+/-) mice. Large tumors often resulted in intestinal intussusception and early death of APC(min/+)PTEN(+/-) mice. Targeted array revealed that osteopontin (OPN) was the leading gene whose expression was strongly induced by deficiency of PTEN. In colon cancer cells, gain-of-function mutation of PI3K robustly increased levels of OPN and treatment with OPN reduced growth factor deprivation-induced programmed cell death. Moreover, OPN expression was strongly increased in Ras-induced transformation of intestinal epithelial cells in a PI3K-dependent manner. Inhibition of OPN expression by specific small interfering RNA reduced uncontrolled growth and invasiveness of Ras-transformed intestinal epithelial cells. Thus, our results suggest that the PI3K pathway promotes the transformation of intestinal adenoma to adenocarcinoma. OPN, a downstream effector of PI3K, protects transformed intestinal epithelial cells from programmed cell death and stimulates their anchorage-independent growth.
Shao
Jinyi
J
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Washington
M Kay
MK
Saxena
Romil
R
Sheng
Hongmiao
H
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000236:Adenoma / Q000378:metabolism / Q000473:pathology*; D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002461:Cell Line, Transformed; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D003433:Crosses, Genetic; D011905:Genes, ras / Q000502:physiology; D006579:Heterozygote; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009361:Neoplasm Invasiveness; D053495:Osteopontin / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction
C506896:Spp1 protein, mouse; D053495:Osteopontin; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse