Effect Of Gankyrin On Breast Cancer Metastasis And The Relative Mechanism

Breast cancer is a malignant tumor that severely threatens the health of women. All over the world there are 1,200,000 new patients suffering breast cancer every year, which account for 18% of all the female tumor cases. Meanwhile breast cancer is one of the most metastatic tumors, and metastasis has become the major reason of death. So studies for the metastasis-related mechanisms, new regulators and signallings will be of considerable significance to improve the survival rate and life quality of patients.gankyrin is an oncogene which was identified recently. Initially its expression product, the Gankyrin protein, was found to participate in the regulation of 19S subunit of the 26S proteasomes, while the further research revealed the intimate relationship between Gankyrin and tumorigenesis. Gankyrin was reported to be up-regulated in liver cancer and several hepatoma carcinoma cell lines, and it can induce the transformation of NIH3T3 cells. Then the over expression of Gankyrin was discovered in esophagus squamous cell cancer, colon cancer and pancreatic cancer with immunohistochemistry analysises, which draw much attention to the relationship between Gankyrin and cancer, especially the cancers of digestive tract.Meanwhile, the molecular mechanism of Gankyrin in tumorgenesis is being increasingly understood. Results from several teams, domestic and overseas, showed that Gankyrin can promote the degradation of Rb and P53 through ubiquitin- proteasomes pathway. Other reports demonstrated that Gankyrin can antagonize the anti-tumor function of p16INK4A. Our laboratory initially found that the level of Gankyrin was obviously elevated when the NIH3T3 cell was transformed by Ras, and Gankyrin mediated the tumorgenesis of lung cancer. Our further studies found that Gankyrin can regulate the RhoA-ROCK signalling, wihich finally resulted in the deregulation of PTEN and the sustained activation of PI3K-Akt pathway. So far almost all the studies of Gankyrin have focusd on the tumors of digestive system. There were seldom reports about expression or molecular function of Gankyrin in other systems and organs, or the links between Gankyrin and other tumors (such as breast cancer). So investigating the effect of Gankyrin on breast cancer metastasis and the underlying mechanisms will provide new ideas for cancer metastasis and potential target for cancer therapy.This study firstly examined the expression of Gankyrin in clinical samples from 86 breast cancer patients, and found that the level of Gankyrin in cancer tissues was significantly higher than that in adjacent tissues (P<0.001). More importantly, in the comparison between patients with lymphonode metastasis and non-metastasis, we found the expression of Gankyrin in lymphonode metastasis group was significantly higher than that of non-metastasis group (P<0.001). This result demonstrated the significant correlation between the Gankyrin level and breast cancer metastasis. Then a series of experiments were carried out to observe the effects of Gankyrin on cell migration, invasion, adhesion and other metastasis-related phenotypes. The results showed that Gankyrin can promot the migration of breast cancer cells and facilitate cell invasion toward ECM, and can also inhibite the cell-matrix adhesion. In addition, Gankyrin was found to notablely regulate the polymerization of skeleton protein F-action. In order to explore the molecular mechanisms through which Gankyrin promotes breast cancer metastasis, we examined Gankyrin's effect on the activities of Rho family GTPases. We found that Gankyrin can up-regulate the intra-cellular level of Rac1-GTP and Cdc42-GTP, while down-regulate the RhoA-GTP.To sum up, this study firstly discovered the correlation between Gankyrin level and clinical breast cancer metastasis, then analyzed the effect of Gankyrin on the metastasis-related phenotypes, such as migration, invasion, adhesion and F-action polymerization of breast cancer cells, and found that Gankyrin might exert its metastasis-promoting functions through all these phases mentioned above. All these studies discover new molecular functions of Gankyrin, and provide groundwork and clues for the thorough understanding of the molecular mechanism through which Gankyrin affects breast cancer metastasis.