EFEMP1 inhibits migration of hepatocellular carcinoma by regulating MMP2 and MMP9 via ERK1/2 activity

Abstract

The role of epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) inhibiting migration in hepatocellular carcinoma (HCC) remains unknown. Expression of EFEMP1 in HCC cell lines were quantified by western blotting and real-time PCR. The role of EFEMP1 in HCC cell migration was explored in vitro via siRNA and adding purified EFEMP1 protein. The associated molecule expression was detected by western blotting after downregulation of EFEMP1 and also tested by immunohistochemistry. Eight pairs of HCC non-HCC liver samples and 215 HCC samples were subjected to immunohistochemistry. EFEMP1 was highly expressed in 7,721 and HepG2 HCC cell lines while HuH7 HCC cell line expressed the lowest level of EFEMP1 compared with the others. Downregulating EFEMP1 by siRNA markedly increased the migration ability of HCC cells while adding purified EFEMP1 protein inhibited HCC cell migration. Downregulation of EFEMP1 increased the expression of ERK1/2, MMP2 and MMP9. Furthermore, U0126 (a highly selective and potent inhibitor of pERK1/2) could abrogate the migration ability enhanced by siRNA. Accordingly, MMP2 and MMP9 were inversely expressed with EFEMP1 expression by immunohistochemistry. EFEMP1 downregulated in HCC tissues, and lower EFEMP1 expression was significantly associated with HCC patients with ascites (P=0.050), vascular invasion (P=0.044), poorer differentiation (P=0.002) and higher clinical stage (P=0.003).

Fibulin-4 is associated with prognosis of endometrial cancer patients and inhibits cancer cell invasion and metastasis via Wnt/β-catenin signaling pathway

“…Fibulin-3 was reported to be highly expressed in ovarian cancer [26], osteosarcoma [27], pancreatic cancer [28], cervical cancer [29], and glioma [30], and promoted tumor development. However, in hepatocellular carcinoma [31], gastric cancer [32], lung cancer [33], endometrial carcinoma [34], breast cancer [35], nasopharyngeal carcinoma [36], and glioblastoma [37], fibulin-3 was downregulated, and could inhibit tumor cell proliferation, invasion, and metastasis. Fibulin-5 was widely considered a tumor suppressor gene that inhibited tumor growth, invasion, and angiogenesis in the development of most tumors [38–42].…”

RETRACTED ARTICLE: Fibulin-3 promotes osteosarcoma invasion and metastasis by inducing epithelial to mesenchymal transition and activating the Wnt/β-catenin signaling pathway

“…Functionally, fibulin-3 had the ability to promote cancer cell growth and invasion. However, in hepatocellular carcinoma 14, 15 , gastric cancer 16 , lung cancer 17, 18 , endometrial carcinoma 19 , and nasopharyngeal carcinoma 20 , fibulin-3 was down-regulated in cancer tissues and suppressed cancer cell growth and invasion. In our current study, we investigated the function of fibulin-3 in human osteosarcoma invasion and metastasis, and the the relationship between fibulin-3 and EMT.…”

Fibulin-3 Attenuates Phosphate-Induced Vascular Smooth Muscle Cell Calcification by Inhibition of Oxidative Stress

“…HAoSMCs were grown to confluence and used in all experiments from passages 4 to 10. HAoSMCs were treated for the indicated periods with 2 mM β-glycerophosphate (Sigma Aldrich) [23, 28, 34, 36-38], 200 ng/ml recombinant human Fibulin-3 protein (R&D Systems) [9, 39] or 10 µM H 2 O 2 (Sigma Aldrich) [40-42]. Treatment with 10 mM β-glycerophosphate and 1.5 mM CaCl 2 (Sigma-Aldrich) for 11 days was used as calcification media for the calcium deposition analysis and Alizarin Red staining [43].…”