Up-Regulation of PAI-1 and Down-Regulation of uPA Are Involved in Suppression of Invasiveness and Motility of Hepatocellular Carcinoma Cells by a Natural Compound Berberine.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death and its prognosis remains poor due to the high risk of tumor recurrence and metastasis. Berberine (BBR) is a natural compound derived from some medicinal plants, and accumulating evidence has shown its potent anti-tumor activity with diverse action on tumor cells, including inducing cancer cell death and blocking cell cycle and migration. Molecular targets of berberine involved in its inhibitory effect on the invasiveness remains not yet clear. In this study, we identified that berberine exhibits a potent inhibition on the invasion and migration of HCC cells. This was accompanied by a dose-dependent down-regulation of expression of Cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP)-9 in berberine-treated HCC cells. Furthermore, berberine inactivated p38 and Erk1/2 signaling pathway in HCC cells. Primarily, this may be attributed to the up-regulation of plasminogen activator inhibitor-1 (PAI-1), a tumor suppressor that can antagonize uPA receptor and down-regulation of uPA. Blockade of uPA receptor-associated pathways leads to reduced invasiveness and motility of berberine-treated HCC cells. In conclusion, our findings identified for the first time that inactivation of uPA receptor by up-regulation of PAI-1 and down-regulation of uPA is involved in the inhibitory effect of berberine on HCC cell invasion and migration.
Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang Mid-Road, Shiyan 442000, China. wangxb@hbmu.edu.cn.|Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, 30 South Renmin Road, Shiyan 442000, China. wangxb@hbmu.edu.cn.
Xuanbin
X
Wang
School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China. ckwang@hku.hk.
Ning
N
Wang
Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang Mid-Road, Shiyan 442000, China. hongliangli@hbmu.edu.cn.|Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, 30 South Renmin Road, Shiyan 442000, China. hongliangli@hbmu.edu.cn.
Hongliang
H
Li
Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang Mid-Road, Shiyan 442000, China. liuming@hbmu.edu.cn.|Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, 30 South Renmin Road, Shiyan 442000, China. liuming@hbmu.edu.cn.
Ming
M
Liu
Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang Mid-Road, Shiyan 442000, China. fengjuncao@hbmu.edu.cn.
Fengjun
F
Cao
Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang Mid-Road, Shiyan 442000, China. xjyu@hbmu.edu.cn.
Xianjun
X
Yu
Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang Mid-Road, Shiyan 442000, China. zhangjx@hbmu.edu.cn.
Jingxuan
J
Zhang
Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang Mid-Road, Shiyan 442000, China. tanyan@hbmu.edu.cn.
Yan
Y
Tan
Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, 39 Chaoyang Mid-Road, Shiyan 442000, China. longchaoxiang@hbmu.edu.cn.|Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, 30 South Renmin Road, Shiyan 442000, China. longchaoxiang@hbmu.edu.cn.
Longchao
L
Xiang
School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, China. yfeng@hku.hk.
Yibin
Y
Feng
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001599:Berberine / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis / Q000276:immunology*
D000893:Anti-Inflammatory Agents; D017395:Plasminogen Activator Inhibitor 1; D001599:Berberine; D014568:Urokinase-Type Plasminogen Activator
PAI-1; berberine; hepatocellular carcinoma; invasion; migration; uPA