The Role of Matrix Metalloproteinases in theEpithelial-Mesenchymal Transition of Hepatocellular Carcinoma

The epithelial-mesenchymal transition (EMT) is a transformation process mandatory for the local and distant progression of manymalignant tumors, including hepatocellular carcinoma (HCC). Matrix metalloproteinases (MMPs) play significant roles in cellularregeneration, programmed death, angiogenesis, and many other essential tissular functions, involved in the normal developmentand also in pathological processes, such as the EMT. This paper reviews the roles of MMPs in the EMT involved in HCCinvasion, as well as the ancillary roles that MMP cross-activation and tissue inhibitors play in modulating this process. Whilegelatinases MMP-2 and MMP-9 are the MMPs commonly cited in the EMT of HCC, MMPs belonging to other classes havebeen 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 alsodata suggesting that other MMPs with a suspected or demonstrated role in the EMT of other cancers may also have somedegree of involvement in HCC. The auto- and cross-activation of MMPs may complicate this issue, as pinpointing the extent ofimplication of each MMP may be extremely difficult. The homeostasis between MMPs and their tissue inhibitors is essential inpreventing tumor progression, and the disturbance of this stability is another entailed factor in the EMT of HCC, which isaddressed herein