Translational Regulation in Hepatocellular Carcinogenesis

Abstract

The mortality of hepatocellular carcinoma (HCC) is distributed unevenly worldwide. One of the major causes is hepatitis B or hepatitis C virus infection and the development and progression of liver cirrhosis. The carcinogenesis of HCC is among others regulated via the mTOR (mechanistic target of rapamycin) signaling pathway and represents a possible method of targeted treatment. The aim of our article was to address the most recent clinical advances and findings of basic studies on the mTOR signaling pathway and the involved factors. Risk factors play a key role in dysregulation of the signaling pathway, where both mTORCs are upregulated and protein synthesis is altered. eIFs and, to a lesser extent, eEFs play an essential role in this process. Whether the factor will be upregulated or downregulated, among others, depends on hepatitis B/C virus infection. The amount of a particular factor in a patient sample lets us know whether HCC recurrence will occur, what is the likelihood of chemoresistance, and what outcome is predicted for patients with an increased value. Our analysis shows that in addition to mTOR, eIF3, eIF4, and eIF5 play an important role, as they can serve as biomarkers for non-and virus-related HCC.

Liver cancer cells with nuclear MET overexpression release translation regulatory protein‐enriched extracellular vesicles exhibit metastasis promoting activity

“…Gene expression is regulated primarily at levels of transcription and translation. Deregulation of mRNA translation, especially at the rate‐limiting step of translational initiation, results in a global increase of protein synthesis or selective enhanced translation of oncogenic mRNAs, which may play an important role in cancer development and progression (Bracic Tomazic et al., 2021 ; Robichaud et al., 2019 ; Silvera et al., 2010 ). In HCC, previous studies have reported the enhanced expression of translation factor mRNAs including both EIFs and ribosomal proteins (RPs) (Kondoh et al., 2001 ; Shuda et al., 2000 ).…”

The Translational Bridge between Inflammation and Hepatocarcinogenesis

“…In HCC, 40-50% of patients upregulate the mTORC components [115]. Similarly, many of the downstream mTOR, as well as mTOR-independent eIFs, are reported to be upregulated in HCC [116]. Obviously, these molecules are all key components, with tumor characteristic hallmarks ranging from sustained proliferation to resistance to growth repression.…”

Silvestrol alleviates glioblastoma progression through ERK pathway modulation and MANBA and NRG-1 expression

“…It has been identified as an inhibitor of eukaryotic initiation factor 4A (eIF4A), one of the eukaryotic translation initiation factors, and is noted for its high specificity and tolerability in animal models [8]. The overactivity of translation initiation factors is closely linked to translation dysregulation, a condition that is strongly associated with excessive cell proliferation, angiogenesis, survival, and altered energetics in tumors [9,10]. Consequently, silvestrol has demonstrated the capability to inhibit the growth of numerous cancer cell lines at low nanomolar concentrations [11][12][13][14], especially targeting mRNAs with highly structured 5′UTR that are heavily reliant on eIF4A for translation [15].…”