Abstract
The epithelial-mesenchymal transition (EMT) is a transformation process mandatory for the local and distant progression of many malignant tumors, including hepatocellular carcinoma (HCC). Matrix metalloproteinases (MMPs) play significant roles in cellular regeneration, programmed death, angiogenesis, and many other essential tissular functions, involved in the normal development and also in pathological processes, such as the EMT. This paper reviews the roles of MMPs in the EMT involved in HCC invasion, as well as the ancillary roles that MMP cross-activation and tissue inhibitors play in modulating this process. While gelatinases MMP-2 and MMP-9 are the MMPs commonly cited in the EMT of HCC, MMPs belonging to other classes have been proven to be involved in this process, favoring not only invasion and metastasis (MMP-1, MMP-3, MMP-7, MMP-10, MMP-11, MMP-13, MMP-14, MMP-16, MMP-26, and MMP-28) but also angiogenesis (MMP-8 and MMP-10). There is also data suggesting that other MMPs with a suspected or demonstrated role in the EMT of other cancers may also have some degree of involvement in HCC. The auto- and cross-activation of MMPs may complicate this issue, as pinpointing the extent of implication of each MMP may be extremely difficult. The homeostasis between MMPs and their tissue inhibitors is essential in preventing tumor progression, and the disturbance of this stability is another entailed factor in the EMT of HCC, which is addressed herein.
Highlights
Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide and develops in a context of long-term liver injury, inflammation, and regeneration [1]
A number of transcription factors are involved in the Epithelial-mesenchymal transition (EMT) of HCC, including Snail, Twist, and zinc finger E-box binding protein 1 (ZEB1), and their presence is associated with a poor prognosis [29,30,31]
The Matrix metalloproteinases (MMPs) gene family is upregulated by Snail expression in HepG2 cells in candidate genes relating to tumor migration; MMPs may play an important part in the EMT of HCC [39]
Summary
Hepatocellular carcinoma (HCC) is one of the leading causes of death worldwide and develops in a context of long-term liver injury, inflammation, and regeneration [1]. EMT is considered essential for oncogenesis, enabling tumors to acquire aggressive features such as invasiveness and the ability to metastasize [8]. MMPs promote a wide spectrum of processes, including cell proliferation and migration, and could play a role in cell apoptosis, angiogenesis, tissue regeneration, and immune response [9]. In malignancies, such as HCC, MMPs function within the tumor microenvironment to induce changes during EMT and help to facilitate EMT via invasion and metastasis behaviors [10]. MMPs seem to play important roles, as the members of this family have various implications in the complex pathogenesis of EMT in HCC. This paper is aimed at thoroughly presenting their functions in this process
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