Expression and inhibitory role of TIMP-3 in hepatocellular carcinoma

Abstract

Abstract. As a member of the tissue inhibitor of metalloproteinases (TIMP) family, it has been reported that TIMP-3 is involved in human cancer development. However, the function of TIMP-3 in hepatocellular carcinoma (HCC) development is unclear. We aimed to determine the biological role of TIMP-3 in HCC by evaluating the effects of its methylation status and expression on HCC cell function. TIMP-3 expression in HCC tissues was visibly analyzed by immunohistochemistry. Methylation of the TIMP-3 promoter was evaluated by methylation-specific PCR. Effects of TIMP-3 on HCC cell growth, apoptosis, migration, and invasion were examined by transfecting the TIMP-3-expressing plasmid, pCMV6. TIMP-3 was expressed in non-tumorous live tissue, but silenced or downregulated in 60% of HCC cases (P<0.05). Reduced protein expression of TIMP-3 was associated with reduced tumor differentiation (P=0.003) and increased metastatic activity (P=0.005) in HCC cell lines. Promoter methylation contributed to the TIMP-3 inactivation. Overexpression of TIMP-3 in HCC cell lines suppressed cell proliferation, induced apoptosis, and inhibited migration and invasion in vitro. TIMP-3 expression is suppressed by promoter methylation in HCC. This inhibitory protein acts as a functional tumor suppressor by inhibiting HCC cell proliferation, invasion, and migration and by inducing apoptosis and cell cycle arrest at the G2/M phase.

Overexpression of TIMP3 Protects Against Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Apoptosis Through ROS/Mapks Pathway

“…Hence, inhibition of cardiomyocyte apoptosis can ameliorate myocardial dysfunction after I/R injury and limit myocardial remodeling development [32]. Although previous studies have revealed that TIMP3 plays an important role in regulating apoptotic activity in certain cancers [33, 34], prior to present study, it is unclear whether TIMP3 is involved in myocardial apoptosis undergoing I/R injury. The present data demonstrated that upregulation of TIMP3 inhibited myocardial apoptosis, as evidenced by reduced TUNEL-positive cells.…”

Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma

“…Furthermore, the effects of TIMP3 on cancer progression appeared to be context dependent in several studies 38 , 39 . However, in HCC studies TIMP3 expression was generally reported as decreased and among genes involved in a favorable survival in experimental models 19 , 40 , 41 . Consistently, it has been reported that ADAM17 activity is increased in HCC 42 .…”

Distinctive pattern of AHNAK methylation level in peripheral blood mononuclear cells and the association with HBV‐related liver diseases

“…Our previous study found that the host immune system of liver cancer has unique DNA methylation characteristics, and significant changes of methylation in blood are expected to be noninvasive markers for early diagnosis of liver cancer . However, there are few studies on the abnormal DNA methylation of single gene in liver cancer …”

“…16 However, there are few studies on the abnormal DNA methylation of single gene in liver cancer. 17 AHNAK is a desmosomal connexin, located in chromosome 11: 62433542-62556235, encoding 700 kDa protein, and is expressed in all kinds of cancer cells. 18,19 It has been reported that low expression of AHNAK can effectively inhibit breast cancer cell invasion and proliferation as a tumor suppressor.…”