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 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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies due to underlying co-morbid cirrhosis and chemo-resistance
Many growth factor receptors such as epidermal growth factor receptor (EGFR), plateletderived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and fibroblast growth factor receptor (FGFR) as well as key oncogenic signaling pathways related to proliferation and angiogenesis such as Ras/Raf/MEK/ERK (MAPK), phoshoinositol-3 kinase (PI3k)/Akt/mTOR, hepatocyte growth factor (HGF)/c-mesenchymal epithelial transition factor (c-Met), insulin growth factor receptor(IGF), transforming growth factor-β (TGF-β), Wnt/β-catenin, Hedgehog and Notch have been shown to be involved in hepatocarcinogenesis [2,3]
One mechanism of sorafenib resistance in cultured HCC cells may be associated with a switch from the MAPK pathway to the parallel PI3K/Akt pathway when vascular endothelial growth factor receptor (VEGFR), plateletderived growth factor receptor (PDGFR), Ret, c-kit and the downstream MAPK pathway are inhibited by sorafenib inhibition of tyrosine kinases
Summary
Deleted FOXM1 mouse hepatocytes are highly resistant to developing HCC in response to a Diethylnitrosamine (DEN)/Phenobarbital (PB) liver tumor-induction protocol suggesting a pivotal role for FOXM1 in HCC development [23,24]. Induction of MMP-7, RhoC, and ROCK1 expression by FOXM1 can promote hepatoma cell invasion and metastasis [25]. FOXM1 expression was highly correlated with the recurrence and poor survival of patients with HBV-HCC after surgical resection. Another downstream effector of FOXM1, acid phosphatase 5 (ACP5), is involved in progression and metastasis of HCC mediated by FOXM1. Co-expression of ACP5 and FOXM1 was associated with poor prognosis. Further analysis revealed the relevance of miR-135a with respect to the prognosis and survival of HCC patients with. PVTT has been correlated with poor prognosis of hepatocellular carcinoma and 50%–80% of HCC is accompanied by portal vein invasion. MiR-135a is highly over-expressed in PVTT [27]
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