The phosphatases PTEN and INPP4B are frequently deregulated in human cancer and have been proposed to act as tumor suppressor genes by coordinately antagonizing PI3K/AKT signaling. While the function of PTEN has been extensively studied, little is known about the underlying molecular mechanisms by which INPP4B exerts its tumor suppressive function. Additionally, its role in tumorigenesis in vivo has not been studied.
Here, we show that a partial or complete loss of the phosphatase function of Inpp4b morphs benign thyroid adenoma lesions observed in Pten heterozygous mice into lethal and metastatic follicular-like thyroid cancer (FTC) (Chapter 2). Importantly, analysis of human thyroid cancer cell lines and specimens reveals that INPP4B expression is downregulated in FTC. Mechanistically, we have found that INPP4B, but not PTEN, is enriched in the early endosomes of thyroid cancer cells, where it blocks PI3K-C2 mediated AKT2 activation and in turn tumor proliferation and anchorage-independent cell growth. Taken together, these data identify INPP4B as a novel tumor suppressor in FTC oncogenesis and metastasis through localized regulation of PI3K/AKT pathway at the endosomes.
Further, we present evidence that INPP4B downregulation cooperates with PTEN loss in prostate cancer progression and metastasis (Chapter 3). In vivo, a partial loss of Inpp4b cooperates with Pten haploinsufficiency to promote prostate tumorigenesis. In vitro, we have found that knockdown of INPP4B in cell lines increased their migratory and invasive properties. Overall, our studies have greatly increased our understanding of the molecular mechanisms of the tumor suppressive functions of INPP4B and provided in vivo evidence for the cooperation of Inpp4b with Pten haploinsufficiency in both thyroid and prostate tumorigenesis / Medical Sciences
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/17467234 |
| Date | January 2015 |
| Creators | Chew, Chen Li |
| Contributors | Roberts, Thomas, Zhao, Jean, Di Cristofano, Antonio |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | English |
| Detected Language | English |
| Type | Thesis or Dissertation, text |
| Format | application/pdf |
| Rights | embargoed |
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