Overexpression of Cathepsin Z Contributes to Tumor Metastasis by Inducing Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma
Open Access
- 22 September 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (9), e24967
- https://doi.org/10.1371/journal.pone.0024967
Abstract
The aim of this study was to characterize the oncogenic function and mechanism of Cathepsin Z (CTSZ) at 20q13.3, a frequently amplified region in hepatocellular carcinoma (HCC). Real-time PCR were used to compare CTSZ expression between paired HCC tumor and non-tumor specimens. CTSZ gene was stably transfected into HCC line QGY-7703 cells and its role in tumorigenicity and cell motility was characterized by soft agar, wound-healing, transwell invasion and cell adhesion assay, and tumor xenograft mouse model. Western blot analysis was used to study expression of proteins associated with epithelial-mesenchymal transition (EMT). Upregulation of CTSZ was detected in 59/137 (43%) of primary HCCs, which was significantly associated with advanced clinical stage (P = 0.000). Functional study found that CTSZ could increase colony formation in soft agar and promote cell motility. Further study found that the metastatic effect of CTSZ was associated with its role in inducing epithelial-mesenchymal transition (EMT) by upregulating mesenchymal markers (fibronectin and vimentin) and downregulating epithelial markers (E-cadherin and α-catenin). In addition, CTSZ could also upregulate proteins associated with extracellular matrix remodeling such as MMP2, MMP3 and MMP9. Taken together, our data suggested that CTSZ was a candidate oncogene within the 20q13 amplicon and it played an important role in HCC metastasis.Keywords
This publication has 28 references indexed in Scilit:
- Cellular senescence induced by cathepsin X downregulationEuropean Journal of Cell Biology, 2011
- Cysteine Proteases Bleomycin Hydrolase and Cathepsin Z Mediate N-terminal Proteolysis and Toxicity of Mutant HuntingtinPublished by Elsevier BV ,2011
- Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in miceProceedings of the National Academy of Sciences of the United States of America, 2010
- Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancerThe Journal of Pathology, 2008
- Cathepsins and osteosarcoma: Expression analysis identifies cathepsin K as an indicator of metastasisMolecular Carcinogenesis, 2007
- Mesenchyme Forkhead 1 ( FOXC2 ) plays a key role in metastasis and is associated with aggressive basal-like breast cancersProceedings of the National Academy of Sciences of the United States of America, 2007
- HOXB7, a Homeodomain Protein, Is Overexpressed in Breast Cancer and Confers Epithelial-Mesenchymal TransitionCancer Research, 2006
- Up‐regulation of cathepsin X in Helicobacter pylori gastritis and gastric cancerThe Journal of Pathology, 2005
- Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor MetastasisCell, 2004
- New functions for the matrix metalloproteinases in cancer progressionNature Reviews Cancer, 2002