Gankyrin promotes tumor growth and metastasis through activation of IL-6/STAT3 signaling in human cholangiocarcinoma
| Autor: | Yingjian Liang, Yuejin Li, Nishant Bhatta, Zhaoyang Lu, Shuai Li, Shu-Yi Qi, Xiang Fang, Xiaohe Luo, Shangha Pan, Ruipeng Song, Tiemin Pei, Lianxin Liu, Xuehui Hong, Xuan Song, Tongsen Zheng, Changming Xie, Jiabei Wang, Jiaren Liu, Hongchi Jiang, Boshi Sun, Dalong Yin |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
STAT3 Transcription Factor
Proteasome Endopeptidase Complex Small interfering RNA Gankyrin medicine.disease_cause Retinoblastoma Protein Metastasis Cholangiocarcinoma Cell Movement Predictive Value of Tests Proto-Oncogene Proteins parasitic diseases medicine Humans Neoplasm Invasiveness STAT3 Gene knockdown Hepatology biology Interleukin-6 Cell growth Cell Cycle Checkpoints Prognosis medicine.disease Gene Expression Regulation Neoplastic Bile Ducts Intrahepatic Bile Duct Neoplasms biology.protein STAT protein Cancer research Carcinogenesis Signal Transduction |
| Zdroj: | Hepatology. 59:935-946 |
| ISSN: | 0270-9139 |
| DOI: | 10.1002/hep.26705 |
| Popis: | Although gankyrin is involved in the tumorigenicity and metastasis of some malignancies, the role of gankyrin in cholangiocarcinoma (CCA) is unclear. In this study we investigated the expression of gankyrin in human CCA tissues and cell lines. The effects of gankyrin on CCA tumor growth and metastasis were determined both in vivo and in vitro. The results showed that gankyrin was overexpressed in CCA tissues and cell lines. Gankyrin expression was associated with CCA histological differentiation, TNM stage, and metastasis. The multivariate Cox analysis revealed that gankyrin was an independent prognostic indicator for overall survival. Gankyrin overexpression promoted CCA cell proliferation, migration, and invasion, while gankyrin knockdown inhibited CCA tumor growth, metastasis, and induced Rb-dependent senescence and G1 phase cell cycle arrest. Gankyrin increased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and promoted the nuclear translocation of p-STAT3. Suppression of STAT3 signaling by small interfering RNA (siRNA) or STAT3 inhibitor interfered with gankyrin-mediated carcinogenesis and metastasis, while interleukin (IL)-6, a known upstream activator of STAT3, could restore the proliferation and migration of gankyrin-silenced CCA cells. The IL-6 level was decreased by gankyrin knockdown, while increased by gankyrin overexpression. Gankyrin regulated IL-6 expression by way of facilitating the phosphorylation of Rb; meanwhile, rIL-6 treatment increased the expression of gankyrin, suggesting that IL-6 was regulated by a positive feedback loop involving gankyrin in CCA. In the xenograft experiments, gankyrin overexpression accelerated tumor formation and increased tumor weight, whereas gankyrin knockdown showed the opposite effects. The in vivo spontaneous metastasis assay revealed that gankyrin promoted CCA metastasis through IL-6/STAT3 signaling pathway. Conclusion: Gankyrin is crucial for CCA carcinogenesis and metastasis by activating IL-6/STAT3 signaling pathway through down-regulating Rb protein. (Hepatology 2014;59:935–946) |
| Databáze: | OpenAIRE |
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