Carcinogenesis Advance Access originally published online on August 11, 2007
Carcinogenesis 2007 28(12):2476-2483; doi:10.1093/carcin/bgm186
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Heterozygous disruption of the PTEN promotes intestinal neoplasia in APCmin/+ mouse: roles of osteopontin
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
1 Department of Pathology, Vanderbilt University, Nashville, TN 37232, USA
2 Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
* To whom correspondence should be addressed. Tel: +317-274-2630; Fax: +317-274-7334;Email: hsheng{at}iupui.edu
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 APCmin/+ mice. Number and size of intestinal tumors were significantly increased in mice bearing both adenomatous polyposis coli (APC) and PTEN mutations. While APCmin/+PTEN+/+ mice developed adenomas, invasive carcinomas developed in APCmin/+PTEN+/– mice. Large tumors often resulted in intestinal intussusception and early death of APCmin/+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.
Abbreviations: ELISA, enzyme-linked immunosorbent assay; IPTG, isopropyl-1-thio-β-D-galactopyranoside; mRNA, messenger RNA; OPN, osteopontin; RT–PCR, reverse transcription–polymerase chain reaction; siRNA, small interfering RNA
Received April 5, 2007; revised August 3, 2007; accepted August 5, 2007.
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