Colorectal cancer (CRC) is the 3rd common cancer in the world. Because the five-year survival rate is below 60 % in the patients with CRC, two important respects in CRC researches are early diagnosis and more effective chemotherapeutic drugs. In fact, the studies on molecular pathology of CRC can resolve these two problems. Insulin has a role in the carcinogenesis and developments of CRC, and 5-FU is a standard chemotherapeutic drug for the patients with stage III CRC. As a human securin, PTTG has a major role in many functions. In our studies of 2-D proteomics, PTTG correlates with the invasiveness of CRC. Besides, it is found to be highly expressed in many types of cancer, but the expression of PTTG is, however, low or undetectable in normal tissues. This character of tumor-specific expression is suitable for drug and target therapy. Therefore, we use cell line HT-29 to study the effects of 5-FU and insulin on the expression of PTTG. We have found that insulin in the physiologic level up-regulates PTTG. In normal physiologic level, insulin up-regulates PTTG, in a dose-dependent manner. On the other hand, the induction of PTTG by insulin more than normal physiologic level is decreased. In the studies with 5-FU, PTTG has a higher level after treatment, but not in dose-dependent manner. The up-regulation of PTTG by 5-FU is decreased in a higher dose. In cancer cells, insulin regulated pathways may contribute to the growth, proliferation, and apoptosis of tumors by activating oncogenic molecular targets such as PTTG. We have showed that insulin of bio-physiologic level can up-regulate PTTG in colon cancer HT-29 cell lines. Induction of PTTG by insulin suggests a mechanism by which insulin may contribute to the development and/or progression of colon cancers. To tumor- specific expression of PTTG, induction of PTTG by insulin, consequently, may be a target of colon cancer treatment. In the studies of 5-FU and PTTG, we have found that 5-FU in HT-29 cells can induce PTTG, with a peak effect in a dose around IC50. Interestingly, the induction of PTTG is decreased in a higher dose of 5-FU. This is a new finding in the effect of 5-FU on PTTG. Accordingly, we can realize why PTTG in some studies is suppressed; the others have a higher level. More importantly, the connection of PTTG expression between sister chromatic separation and DNA repair after DNA damage is more reasonable. Based on this finding, we propose that PTTG connects DNA damage response pathways, sister chromatic separation and apoptosis after DNA damage. Therefore, PTTG has a key role after DNA damage, deciding cells to have DNA repair/cell cycle arrest or to progress to apoptosis.
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0625106-200042 |
| Date | 25 June 2006 |
| Creators | Hsieh, Cheng-Hsiu |
| Contributors | Yow-Ling Shiue, Hsueh-Wei Chang, Hurng-Wern Huang |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | Cholon |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0625106-200042 |
| Rights | withheld, Copyright information available at source archive |
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