PUBLICATION
Thioredoxin interacting protein promotes invasion in hepatocellular carcinoma
- Authors
- Gunes, A., Bagirsakci, E., Iscan, E., Cakan-Akdogan, G., Aykutlu, U., Senturk, S., Ozhan, G., Erdal, E., Nart, D., Barbet, F.Y., Atabey, N.
- ID
- ZDB-PUB-190113-5
- Date
- 2018
- Source
- Oncotarget 9: 36849-36866 (Journal)
- Registered Authors
- Cakan-Akdogan, Gülcin
- Keywords
- EMT, HCC, TXNIP, metastasis, oxidative stress
- MeSH Terms
- none
- PubMed
- 30627326 Full text @ Oncotarget
Citation
Gunes, A., Bagirsakci, E., Iscan, E., Cakan-Akdogan, G., Aykutlu, U., Senturk, S., Ozhan, G., Erdal, E., Nart, D., Barbet, F.Y., Atabey, N. (2018) Thioredoxin interacting protein promotes invasion in hepatocellular carcinoma. Oncotarget. 9:36849-36866.
Abstract
Background Considerable evidence suggests that oxidative stress plays an essential role in the progression of hepatocellular carcinoma (HCC). While acquired resistance to oxidative stress is the main driver of aggressive cell phenotype, the underlying mechanisms remain unknown. Here, we tested the hypothesis that elevated expression of Thioredoxin-interacting protein (TXNIP) is a main regulator of the aggressive phenotype in HCC.
Materials and methods To test this hypothesis, we measured TXNIP expression levels in 11 HCC cell lines by qPCR and western blotting. In addition, 80 pairs of HCC tissues and matched liver tissues of 73 cases, as well as 11 normal liver tissue samples were examined by immunohistochemistry. Besides, TXNIP expression levels were analyzed by Oncomine Platform in seven independent microarray datasets. Finally, the functional role of TXNIP in HCC was investigated in vitro and in vivo by silencing and overexpression studies.
Results Our results show that TXNIP expression is significantly increased in HCC compared to non-tumor counterparts (p < 0.0001) as well as to normal (p < 0.0001) and cirrhotic (p < 0.0001) liver tissues. Moreover, stable overexpression of TXNIP in HCC cells (i) significantly increases ROS levels, (ii) induces EMT phenotype, (iii) increases motility, invasion and 3D branching tubulogenesis, (iv) decreases apoptosis, and (v) elevates in vivo metastasis in zebrafish embryos. Finally, we identify sinusoidal/stromal and cytoplasmic TXNIP staining patterns as risk factors for intrahepatic vascular invasion (p:0.0400).
Conclusion Our results strongly suggest that overexpression of TXNIP has a pivotal role in HCC progression by inducing cell survival, invasion, and metastasis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping