Abstract 3874: Functional association of MDM2 Binding Protein with migratory and metastatic potential of hepatocellular carcinoma.
Authors: Bi Qian , Fan Rui , Agarwal Neeraj , Iyer Swathi V. , Ding Jie , Iwakuma Tomoo 
Published: August 2014

Hepatocellular carcinoma (HCC) is a rising cause of cancer-related death in the United States with a 5-year survival rate below 12%. The leading cause of this poor prognosis is metastatic spread. Therefore, defining mechanism(s) that facilitate HCC metastasis and the discovery of reagents that suppress metastasis, would be greatly beneficial for HCC patients. The mouse double minute (MDM2) oncogene, a major inhibitor of tumor suppressor p53, has p53-independent roles in cancer progression. In approximately 30% of HCC cases, MDM2 overexpression is detected and is associated with invasion and metastasis in HCC, as well as its poor prognosis. However, the mechanisms underlying MDM2-mediated cancer metastasis remains unsolved. Through the efforts to elucidate the mechanisms behind p53-independent roles of MDM2 in tumorigenesis, MDM2 Binding Protein (MTBP) was identified as a protein that binds to MDM2. Overexpression of MTBP leads to p53-independent cell proliferation arrest, which is in turn blocked by simultaneous overexpression of MDM2. We previously found that MTBP suppresses cancer metastasis independently of p53 through the following findings: 1) MTBP haploinsufficiency in mice increases metastasis of hepatocellular carcinoma (HCC), breast cancer, and osteosarcoma; 2) MTBP overexpression inhibits migration and metastasis of p53-null osteosarcoma cells without altering primary tumor growth, indicating that MTBP functions as a metastasis suppressor in osteosarcoma; 3) MTBP endogenously binds to alpha-actinin-4 (ACTN4), an actin-crosslinking protein that increases cell motility, and inhibits the migration and filopodia formation mediated by ACTN4. Vlatković et al. also demonstrated that reduced MTBP expression in head and neck squamous cell carcinoma tissues is associated with reduced survival of patients. Based on these observations, we hypothesize that MTBP plays a crucial role in the suppression of HCC metastasis. To test this hypothesis, we examined MTBP expression in human HCC tissues and the effects of MTBP manipulation on HCC cell migration. We found that 1) MTBP mRNA expression was significantly reduced in HCC tissues as compared with that in surrounding normal tissues, 2) reduced MTBP protein expression in human HCC tissues was associated with the presence of invasion and lymph node metastasis, 3) MTBP overexpression inhibited the migratory potential of several HCC cell lines, whereas its downregulation increased the migration of these cells. These results suggest that MTBP may function as a metastasis suppressor in HCC as well. We have been examining the effects of manipulation of MTBP expression on the in vivo metastasis, ACTN4-dependency, and metastasis-related signaling in HCC cells. Completion of this study will provide a novel mechanism underlying HCC metastasis and may propose MTBP as a potential biomarker for HCC progression.

Citation Format: Qian Bi, Rui Fan, Neeraj Agarwal, Swathi V. Iyer, Jie Ding, Tomoo Iwakuma. Functional association of MDM2 Binding Protein with migratory and metastatic potential of hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3874. doi:10.1158/1538-7445.AM2013-3874