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Role of MTDH, FOXM1 and microRNAs in Drug Resistance in Hepatocellular Carcinoma

Department of Obstetrics and Gynecology, The University of Iowa, Iowa City, IA 52242, USA
Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Department of Internal Medicine, The University of Iowa, Iowa City, IA 52242, USA
Author to whom correspondence should be addressed.
Diseases 2014, 2(3), 209-225;
Received: 16 April 2014 / Revised: 24 June 2014 / Accepted: 25 June 2014 / Published: 1 July 2014
(This article belongs to the Special Issue Targeted Therapy of Hepatocellular Carcinoma: Present and Future)
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies due to underlying co-morbid cirrhosis and chemo-resistance. Vaccination and improved treatment for hepatitis are the most effective means to reduce the burden of liver cancer worldwide. Expression of biomarkers such as AFP (alpha-fetoprotein), DDK1 (Dickkopf WNT Signaling Pathway Inhibitor 1) and microRNAs in blood are being tested for early screening of liver cancer. Since 2008, sorafenib has been used as the standard molecular targeting agent for HCC. However, overall outcomes for sorafenib alone or in combination with other tyrosine kinase inhibitors are unsatisfactory. Whether simultaneously or sequentially, addiction switches and compensatory pathway activation in HCC, induced by sorafenib treatment, may induce acquired resistance. Forkhead box M1 (FOXM1) and metadherin (MTDH) have been shown to be master regulators of different aspects of tumorigenesis, including angiogenesis, invasion, metastasis and drug resistance. Elevated expression of both FOXM1 and MTDH is known to be a consequence of both activating mutations in oncogenes such as PI3K, Ras, myc and loss of function mutations in tumor suppressor genes such as p53 and PTEN in various types of cancers including HCC. The role of FOXM1 and MTDH as potential prognostic markers as well as therapeutic targets in HCC will be discussed. In addition, microRNAs (miRNAs), endogenous small non-coding RNAs involved in the regulation of gene expression, are involved in HCC and interact with both FOXM1 and MTDH in several ways. Thus, altered expression of miRNAs in HCCs will also be discussed as potential tools for diagnosis, prognosis and therapy in HCC. View Full-Text
Keywords: hepatocellular carcinoma (HCC); MTDH; FOXM1; miRNAs hepatocellular carcinoma (HCC); MTDH; FOXM1; miRNAs
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Meng, X.; Devor, E.J.; Yang, S.; Schickling, B.M.; Leslie, K.K. Role of MTDH, FOXM1 and microRNAs in Drug Resistance in Hepatocellular Carcinoma. Diseases 2014, 2, 209-225.

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