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Review

Murine double minute 2, a potential p53-independent

regulator of liver cancer metastasis

Atul Ranjan, Kaustav Bera, Tomoo Iwakuma

Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.

ABSTRACT
Hepatocellular carcinoma (HCC) has emerged as one of the most commonly diagnosed forms of human cancer; yet, the
mechanisms underlying HCC progression remain unclear. Unlike other cancers, systematic chemotherapy is not effective
for HCC patients, while surgical resection and liver transplantation are the most viable treatment options. Thus, identifying
factors or pathways that suppress HCC progression would be crucial for advancing treatment strategies for HCC. The murine
double minute 2 (MDM2)-p53 pathway is impaired in most of the cancer types, including HCC, and MDM2 is overexpressed
in approximately 30% of HCC. Overexpression of MDM2 is reported to be well correlated with metastasis, drug resistance,
and poor prognosis of multiple cancer types, including HCC. Importantly, these correlations are observed even when p53 is
mutated. Indeed, p53-independent functions of overexpressed MDM2 in cancer progression have been suitably demonstrated.
In this review article, we summarize potential effectors of MDM2 that promote or suppress cancer metastasis and specifically
discuss the p53-independent roles of MDM2 in liver cancer metastasis from clinical as well as biological perspectives.
Key words: Murine double minute 2; metastasis; effectors; hepatocellular carcinoma; p53 independent

Address for correspondence:
Dr. Tomoo Iwakuma, 3901 Rainbow Blvd, Wahl Hall East 2005, KS 66160, USA. E-mail: tiwakuma@kumc.edu
Received: 28-12-2015, Accepted: 11-01-2016

INTRODUCTION cascades including detachment of cancer cells from primary
tumors, migration, intravasation, survival in the vasculature,
Liver cancer is the 5th most frequently diagnosed cancer extravasation, and colonization at a secondary site. Multiple
[7]
worldwide in males (9th in females) and is the 2nd leading factors play a role in each metastatic step and the inhibition
cause of cancer-related death in males (6th in females). of any of these steps would be helpful in blocking the cancer
[1]
Around 80% of hepatocellular carcinoma (HCC) cases occur spread. Although distant metastasis is not a common event
in developing countries, mainly due to the incidence in HCC, HCC often shows vascular invasion, intrahepatic
of hepatitis B and hepatitis C infections. HCC is often colonization, and lymph node metastasis. This is most likely
[2]
diagnosed at late stages, and the 5-year survival rate for due to the dense hepatic vasculature which supports the
metastatic HCC is less than 10% (http://www.cancer.org/ intrahepatic metastasis of HCC. [8]
acs/groups/cid/documents/webcontent/003114-pdf.pdf). [3-5]
Understanding the mechanisms involved in the regulation The murine double minute 2 (MDM2) was originally identified
of HCC metastasis and discovering methods or compounds as a gene which was overexpressed in a spontaneously
to suppress metastasis would be highly beneficial for HCC transformed mouse cell line (3T3-DM), and the gene product
[9]
patients. [6] was found to transform normal cells. The primary function
[10]
of MDM2 is to ubiquitinate the tumor suppressor p53 for
Metastasis is a cellular process which involves multiple
inducing its degradation. Hence, MDM2 overexpression
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DOI: How to cite this article: Ranjan A, Bera K, Iwakuma T. Murine double
10.20517/2394-5079.2015.67 minute 2, a potential p53-independent regulator of liver cancer
metastasis. Hepatoma Res 2016;2:114-21.

© 2016 Hepatoma Research | Published by OAE Publishing Inc. 114