title: Reciprocal activation between MMP-8 and TGF-β1 stimulates EMT and malignant progression of hepatocellular carcinoma.
abstract: The efficiency of surgery in hepatocellular carcinoma (HCC) is limited due to metastasis and recurrence, but the molecular mechanisms are unclear. Here, we show that MMP-8 and TGF-β1 accumulate in highly invasive HCC cell lines and invasive HCC patient tissues. Upregulation of MMP-8 and TGF-β1 correlated with changes in cellular epithelial-mesenchymal transition (EMT) phenotypes and HCC migration and invasion. The expression of TGF-β1 was markedly restored by MMP-8 overexpression in TGF-β1-depleted HCC cells mainly via the activation of PI3K/Akt/Rac1 pathway. Similarly, the expression of MMP-8 was restored by TGF-β1 treatment in MMP-8-depleted HCC cells mainly through the activation of the same PI3K/Akt/Rac1 pathway. MMP-8 expression was significantly related to TGF-β1 expression in HCC patient tissues, and high expression of MMP-8 or TGF-β1 was significantly associated with TNM stage and HCC metastasis. Specifically, patients with high co-expression of MMP-8 and TGF-β1 had a shorter time-to-recurrence than those with low co-expression. Therefore, the reciprocal positive interplay between MMP-8 and TGF-β1 contributes to HCC invasion and metastasis by inducing EMT mainly through the PI3K/Akt/Rac1 pathway.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning 530021, Guangxi, China.
authors.forename: Guihui
authors.initials: G
authors.lastname: Qin
authors.affiliation: Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning 530021, Guangxi, China.
authors.forename: Min
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China.
authors.forename: Junze
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China.
authors.forename: Yiwu
authors.initials: Y
authors.lastname: Dang
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Lung Biology Laboratory, Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Center for Translational Medicine, Guangxi Medical University, Nanning 530021, Guangxi, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning 530021, Guangxi, China. Electronic address: yanglz2005@126.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000096:biosynthesis* / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000378:metabolism; D055815:Young Adult; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C107953:RAC1 protein, human; D053773:Transforming Growth Factor beta1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020784:Matrix Metalloproteinase 8; D020830:rac1 GTP-Binding Protein
keywords: Hepatocellular carcinoma; MMP-8; Metastasis; PI3K/Akt/Rac1 pathway; TGF-β1