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

Abstract

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 noncoding 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. OPEN ACCESS

Role of microRNAs in the development of hepatocellular carcinoma and drug resistance

“…Dysregulation of cell cycle progression and failure of apoptosis/autophagy are classic hallmarks of progression to HCC, as with many types of neoplasia. However, unlike some tumors, such as prostate or breast cancer, that are hormonally driven, dysregulation of key cellular, proliferative and developmental pathways leads to HCC (11). There are no tissue-related, hormone-specific components to target in HCC, making study and treatment of HCC particularly difficult (11).…”

“…In general, HCC is difficult to treat because the lack of liver-specific targets available for therapeutic development. Pathways that are key to HCC development (EGFR, PDGF receptor [PDGFR], fibroblast growth factor receptor [FGFR], MAPK, IFG, and transforming growth factor-beta [TGF-β]) are also vital to many other tissue types (11). MDR is a major mode of acquired HCC resistance, which occurs through a multitude of mechanisms, including hypoxic environment, DNA damage, epithelial-mesenchymal transition (EMT), autophagy, and epigenetic regulation, circumventing shutdown of any single pathway (18).…”

“…Forkhead box protein M1 (FoxM1) is a transcription factor involved in cell cycle progression and proliferation, which is essential for tumorigenic metastatic potential (19). Mouse models in which FoxM1 is deleted demonstrate significant resistance to the development of HCC (11). Expression of FoxM1 in HCC is also linked to recurrence and poor survival (11).…”

“…Mouse models in which FoxM1 is deleted demonstrate significant resistance to the development of HCC (11). Expression of FoxM1 in HCC is also linked to recurrence and poor survival (11). Thiazole compounds and proteasome inhibitors have been demonstrated to repress FoxM1, leading to decreased tumor size in mice (11).…”

“…Expression of FoxM1 in HCC is also linked to recurrence and poor survival (11). Thiazole compounds and proteasome inhibitors have been demonstrated to repress FoxM1, leading to decreased tumor size in mice (11). A DNA damage response-related protein, metadherin (MTDH), is believed to be linked to DNA repair through binding of RNA, and high levels of MTDH are expressed in HCC (11).…”