Hepatocyte growth factor (HGF) upregulates heparanase expression via the PI3K/Akt/NF-κB signaling pathway for gastric cancer metastasis.
Heparanase (HPA) is an endoglucuronidase that can promote the shedding of associated cytokines in several types of tumors. However, little is known about what controls the expression of HPA or its role in gastric cancer. In this study, we report for the first time that HGF regulates HPA expression to promote gastric cancer metastasis. In this study, HGF and HPA were found to be significantly expressed in 58 gastric cancer patients. High expression of both HGF and HPA was positively associated with TNM stage, invasion depth and poor prognosis. In MKN74 cells, exogenous HGF significantly increased HPA expression at both the mRNA and protein levels. Further study revealed that HGF first activated PI3K/Akt signaling. NF-κB signaling was activated downstream of PI3K/Akt and promoted HPA expression. However, when c-met, PI3K/Akt or NF-κB signal inhibitors were used, HPA expression was significantly decreased. All of these results indicate that HGF regulates HPA expression by PI3K/Akt and downstream NF-κB signaling. Using bioinformatics and the ChIP assay, p65 was observed to bind to the HPA promoter. Furthermore, HGF significantly induced tumor cell migration, whereas treatment with an NF-κB inhibitor decreased migration. Moreover, when HPA was overexpressed in MKN74 cells, migration was significantly enhanced, and the HGF concentration was increased. However, when HPA was down-regulated in MKN45 cells, migration and HGF levels decreased. Together, these results demonstrate that HGF/c-met can activate PI3K/Akt and downstream NF-κB signaling to promote HPA expression and subsequent tumor metastasis.
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Ning-Bo
NB
Hao
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Bo
B
Tang
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Guo-Zheng
GZ
Wang
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Rui
R
Xie
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Chang-Jiang
CJ
Hu
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Su-Min
SM
Wang
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Yu-Yun
YY
Wu
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
En
E
Liu
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China. Electronic address: xiexia0128@163.com.
Xia
X
Xie
Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China. Electronic address: shimingyang@yahoo.com.
Shi-Ming
SM
Yang
D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D015996:Survival Rate; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014945:Wound Healing / Q000187:drug effects; D000099175:Heparanase
D005966:Glucuronidase; D017228:Hepatocyte Growth Factor; D008156:Luciferases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D000099175:Heparanase
Gastric cancer; HGF; Heparanase; NF-κB; PI3K/Akt