The Role of Matrix Metalloproteinases in the Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma

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.

The crosstalk between circular RNAs and the tumor microenvironment in cancer metastasis

“…MMPs can be produced by stromal and tumor cells. Specifically, MMP13 expression is mainly observed in CAFs, but this enzyme may also be synthesized by other cells to promote invasiveness and angiogenesis [26]. MMP10 supports lung cancer development and metastasis [27].…”

Cancer-Associated Stemness and Epithelial-to-Mesenchymal Transition Signatures Related to Breast Invasive Carcinoma Prognostic

“…A panel of five genes (CXCL12, IGF1, LEF1, MMP1, and RACGAP1) was proposed as biomarkers for prognosis through the survival analysis of BRCA [ 27 ]. MMPs are rather considered as target genes of EMT pathways and MMP expression as a late event of the EMT, being interconnected with key transcription factors, such as Snail, ETS, and β-catenin [ 28 , 29 ].…”

Cannabinoids in the Pathophysiology of Skin Inflammation

“…However, the tumor microenvironment includes an inflammatory component, consisting of leukocytes, cytokines, and various signaling and transcription factors, that aid cancer survival, tumor development, metastasis, and therapy resistance [159]. Among these components, TGF-β can cause immunosuppression and promote tumor growth and survival, TNF-α is involved in cellular transformation, survival, and proliferation, while MMPs can favor tumor invasion through epithelial-mesenchymal transition in many cancers; all these molecules are found in the intersecting pathways of inflammation and carcinogenesis, and cannabinoids can regulate their expression [140,[160][161][162][163][164][165][166]. These common anti-inflammatory and anti-carcinogenic effects of cannabinoids make them excellent candidates for cancer treatment, as they act as the immunomodulatory substances that influence cell signaling in the tumor microenvironment.…”