Phosphatase PRL-3 is a direct regulatory target of TGFβ in colon cancer metastasis

Yanjun Jiang, Xiao Qiong Liu, Ashwani Rajput, Liying Geng, Melanie Ongchin, Qi Zeng, Gregory S. Taylor, Jing Wang

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Metastasis causes most deaths from cancer yet mechanistic understanding and therapeutic options remain limited. Overexpression of the phosphatase PRL-3 (phosphatase of regenerating liver) is associated with metastasis of colon cancer. Here, we show that PRL-3 is a direct target of signaling by TGFb, which is broadly implicated in progression and metastasis. We found that suppression of PRL-3 expression by TGFb was mediated by Smad-dependent inhibition of PRL-3 transcription at the level of promoter activity. PRL-3 activation stimulated PI3K/AKT signaling that caused resistance to stress-induced apoptosis. PRL-3 overexpression promoted metastatic colonization in an orthotopic mouse model of colon cancer, whereas PRL-3 knockdown reduced metastatic potential. Altered metastatic phenotypes were not derivative of primary tumor development or local invasion but could be attributed to PRL-3-mediated cell survival. Our findings suggest that inhibiting PRL-3 expression might be an important mechanism through which TGFb suppresses metastasis in colon cancer. In addition, our findings suggest that loss of TGFb signaling, which occurs commonly during colon cancer progression, is sufficient to activate a PRL-3-mediated cell survival pathway that can selectively promote metastasis. Therefore, a major implication of our findings is that PRL-3 antagonists may offer significant value for antimetastatic therapy in patients with colon cancer.

Original languageEnglish (US)
Pages (from-to)234-244
Number of pages11
JournalCancer Research
Volume71
Issue number1
DOIs
StatePublished - Jan 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Jiang, Y., Liu, X. Q., Rajput, A., Geng, L., Ongchin, M., Zeng, Q., Taylor, G. S., & Wang, J. (2011). Phosphatase PRL-3 is a direct regulatory target of TGFβ in colon cancer metastasis. Cancer Research, 71(1), 234-244. https://doi.org/10.1158/0008-5472.CAN-10-1487