The mouse double minute (MDM2) oncogene enhances cancer metastasis via pathways other than the tumor suppressor p53. However, the mechanisms underlying p53-independent MDM2-mediated cancer progression remain unclear. Through the efforts to understand the p53-independent function of MDM2, MDM2 Binding Protein (MTBP) was identified. We previously demonstrated that MTBP suppresses cancer migration and metastasis independently of p53 through the following findings: 1) MTBP haploinsufficiency in mice increases metastasis of hepatocellular carcinoma (HCC), sarcoma, and other types of cancer; 2) MTBP overexpression inhibits the migration and metastasis of osteosarcoma cells lacking wild-type p53 activity; 3) MTBP endogenously binds to a migration-inducing actin-crosslinking protein alpha-actinin-4 (ACTN4) and inhibits the migration and filopodia formation mediated by ACTN4. Clinically, reduced MTBP expression in head and neck squamous cell carcinoma tissues is shown to be associated with reduced survival of patients. The goal of this proposal is to determine the roles of MTBP and its functional association with MDM2, if any, in cancer metastasis. HCC is a rising cause of cancer-related death in the United States with 5-year survival rate below 12%. The leading cause of this poor prognosis is metastatic spread. For these reasons, we will use HCC as a model for examining the contributions of MDM2 and MTBP in cancer migration and metastasis. Our preliminary results demonstrated the following: 1) reduced MTBP expression in human HCC tissues was associated with the presence of vascular/capsular invasion and lymph node metastasis, 2) MTBP inhibited HCC cell migration, 3) MTBP inhibited the filopodia formation and migration mediated by ACTN4, and 4) MTBP inhibited the activity of Elk-1, an Ets oncogene family transcription factor and a target of Erk1/2 MAP kinase. Based on these observations, we hypothesize that MTBP inhibits HCC metastasis by suppressing ACTN4 and Elk-1 activities; whereas, MDM2 promotes cancer metastasis by its inhibitory binding to MTBP. We will test this hypothesis by achieving the following two Specific Aims:
Aim 1 is to determine the inhibitory effects of MDM2 on the metastasis suppression by MTBP in HCC by exploring downstream mediators of MDM2-MTBP interactions that affect metastasis;
Aim 2 is to determine the in vivo contributions of MDM2 and MTBP to HCC progression in mouse models by using our recently generated hypomorphic MTBPH mice that express MTBP at only 20% of wild-type levels. Completion of this project will fill the knowledge gaps pertaining to the mechanisms by which MTBP inhibits cancer metastasis and MDM2 promotes tumor progression in a p53- independent manner through inhibition of MTBP. Given that reduced MTBP expression is found in about 70% of HCC tissues, MDM2 overexpression is detected in 30% of HCC, and metastasis is the major cause of cancer mortality, our study has the potential to significantly impact the diagnosis, treatment, and prognosis for HCC and likely other types of cancer having altered expression of MDM2 and/or MTBP.

Public Health Relevance

Increased expression of oncoprotein MDM2 and decreased expression of MTBP, an MDM2 binding partner, are associated with cancer spread (metastasis) of hepatocellular carcinoma and other types of human cancer. Completion of this project will fill the knowledge gaps pertaining to the mechanisms by which MTBP inhibits cancer metastasis and MDM2 promotes tumor progression through inhibition of MTBP. Given that metastasis is the major cause of cancer mortality, a study that provides new insights into mechanisms of metastasis will significantly contribute to the improvement of the survival and quality of life of many cancer patients, thereby being relevant to public health.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Ault, Grace S
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University of Kansas
Internal Medicine/Medicine
Schools of Medicine
Kansas City
United States
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Parrales, Alejandro; Thoenen, Elizabeth; Iwakuma, Tomoo (2018) The interplay between mutant p53 and the mevalonate pathway. Cell Death Differ 25:460-470
Ranjan, Atul; Iyer, Swathi V; Ward, Christopher et al. (2018) MTBP inhibits the Erk1/2-Elk-1 signaling in hepatocellular carcinoma. Oncotarget 9:21429-21443
Ranjan, Atul; Iyer, Swathi V; Iwakuma, Tomoo (2017) Suppressive roles of A3AR and TMIGD3 i1 in osteosarcoma malignancy. Cell Cycle 16:903-904
Parrales, Alejandro; Ranjan, Atul; Iwakuma, Tomoo (2017) Unsaturated fatty acids regulate stemness of ovarian cancer cells through NF-?B. Stem Cell Investig 4:49
Link, Tim; Iwakuma, Tomoo (2017) Roles of p53 in extrinsic factor-induced liver carcinogenesis. Hepatoma Res 3:95-104
Dong, Shengli; Baranwal, Somesh; Garcia, Anapatricia et al. (2017) Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase. J Biol Chem 292:16833-16846
Yamamoto, Satomi; Iwakuma, Tomoo (2017) RIPK1-TRAF2 interplay on the TNF/NF-?B signaling, cell death, and cancer development in the liver. Transl Cancer Res 6:94-109
Sasaki, Ken; Kurahara, Hiroshi; Young, Eric D et al. (2017) Genome-wide in vivo RNAi screen identifies ITIH5 as a metastasis suppressor in pancreatic cancer. Clin Exp Metastasis 34:229-239
Kundu, Anup K; Iyer, Swathi V; Chandra, Sruti et al. (2017) Novel siRNA formulation to effectively knockdown mutant p53 in osteosarcoma. PLoS One 12:e0179168
Parrales, Alejandro; Iwakuma, Tomoo (2016) p53 as a Regulator of Lipid Metabolism in Cancer. Int J Mol Sci 17:

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