- Title
- The role of inositol polyphosphate 4-phosphatase II (INPP4B) in the pathogeneis of colon ccancer
- Creator
- Guo, Su Tang
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2018
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Colon cancer is one of the most common and deadly malignancies. Despite recent advances in early diagnosis and the development of novel treatment approaches, the overall survival of patients with metastatic colon cancers remains disappointing. Lots of investigations have discovered some pathways important during the initiation and progression of CRC. These include the WNT, RAS−MAPK, PI3K, TGF-β, P53 and DNA mismatch-repair pathways. But Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway is of particular importance in CRC development, progression and resistance to treatment, since many common genetic and epigenetic anomalies in the disease, such as amplification of epidermal growth factor receptor, activating mutations of KRAS and loss of phosphate and tensin homolog deleted on chromosome 10 (PTEN), converge on activation of PI3K signaling. Lipid and protein kinases promote PI3K signaling, whereas lipid and protein phosphatases suppress PI3K signaling (Manning and Toker, 2017; Newton and Trotman, 2014). Activation of PI3K signaling is negatively regulated by three classes of inositol polyphosphate phosphatases. (Rodgers et al., 2017). The inositol polyphosphate 3-phosphatase (3-phosphatase) PTEN dephosphorylates the 3-position of PI(3,4,5)P3 to generate PI(4,5)P2 (Gericke et al., 2013; Kurokawa et al., 2012), whereas 5-phosphatases, such as Src homology 2-containing inositol 5- phosphatase (SHIP) and phosphatidylinositol 4,5-bisphosphate 5-phosphatase (PIB5PA)/proline-rich inositol polyphosphate phosphatase (PIPP) dephosphorylate the 5-position to produce PI(3,4)P2 (Park et al., 2001). The latter is in turn subjected to dephosphorylation by inositol polyphosphate 4-phosphatase type I (INPP4A) and type II (INPP4B) at the 4-position to generate PI(3)P, thus terminating PI3K signaling. During the past decades, INPP4B has been well established to be a tumor suppressor in a number of cancers. However, we have found that it is frequently upregulated in human colon cancer cells. Silencing of INPP4B blocks activation of Akt and serum- and glucocorticoid-regulated kinase 3 (SGK3), inhibits colon cancer cell proliferation and retards colon cancer xenograft growth. Conversely, overexpression of INPP4B increases proliferation and triggers anchorage-independent growth of normal colon epithelial cells. Moreover, we demonstrate that the effect of INPP4B on Akt and SGK3 is associated with inactivation of phosphate and tensin homolog through its protein phosphatase activity and that the increase in INPP4B is due to Ets-1-mediated transcriptional upregulation in colon cancer cells. To further consolidate the result, two genetically modified mouse model were generated by CRISP/CAS9 technique. The INPP4B+/-; VillinCre+/- mouse strain in which INPP4B expression limited to colon epithelium display increased proliferation potential than wild-type mice. Moreover, these mice appeared to be more sensitive to Colitis induced by Dextran Sulfate Sodium (DSS). Nevertheless, when these mice were crossed with adenomatous polyposis coli (APC) mutant mice, the resulting INPP4B+/-; VillinCre+/-; APC+/- mice exhibited increased tumorigenesis in colon. Although results with these transgenic mouse strains are still under way, the available results strongly support the oncogenic role of INPP4B in colon cancer. In this study, we also discovered and cloned a novel small transcript variant of INPP4B generated by alternative splicing in cells of human colon and breast epithelium origins, which we have named INPP4B-S( INPP4B-short). Moreover, we found that INPP4B-S is translated into a protein product that is located to the cytoplasm and promotes proliferation in colon and breast cancer cells. To the best of our knowledge, this is the first time that INPP4B-S has been cloned and described in detail. It seems that INPP4B-S has an additive effect to INPP4B-FL (INPP4B-full length).
- Subject
- INPP4B; colon cancer; pten; transgenic mice
- Identifier
- http://hdl.handle.net/1959.13/1386333
- Identifier
- uon:32399
- Rights
- Copyright 2018 Su Tang Guo
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
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| View Details Download | ATTACHMENT01 | Thesis | 26 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 106 KB | Adobe Acrobat PDF | View Details Download |