Hypoxia-induced NIPP1 activation enhances metastatic potential and predicts poor prognosis in hepatocellular carcinoma

Autor: Xinying Li, Tiecheng Feng, Zhiming Wang, Yun Huang, Kuan Hu, Yiming Tao, Feng Lin
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Pathology
Metastasis
0302 clinical medicine
Cell Movement
Phosphoprotein Phosphatases
RNA
Small Interfering
Gene knockdown
medicine.diagnostic_test
Liver Neoplasms
EZH2
RNA-Binding Proteins
Hep G2 Cells
General Medicine
Middle Aged
Prognosis
Gene Expression Regulation
Neoplastic
030220 oncology & carcinogenesis
Hepatocellular carcinoma
Immunohistochemistry
Female
RNA Interference
medicine.symptom
medicine.medical_specialty
Carcinoma
Hepatocellular
Biology
03 medical and health sciences
Western blot
Antigens
Neoplasm
Cell Line
Tumor
Endoribonucleases
medicine
Humans
Gene silencing
Enhancer of Zeste Homolog 2 Protein
Neoplasm Invasiveness
Carbonic Anhydrase IX
neoplasms
Cell Proliferation
Interleukin-6
Interleukin-8
Hypoxia (medical)
Hypoxia-Inducible Factor 1
alpha Subunit
medicine.disease
digestive system diseases
Enzyme Activation
030104 developmental biology
Cancer research
Tumor Hypoxia
Zdroj: Tumor Biology. 37:14903-14914
ISSN: 1423-0380
1010-4283
DOI: 10.1007/s13277-016-5392-4
Popis: Hypoxia is known to promote hepatocellular carcinoma (HCC) invasion and metastasis and nuclear inhibitor of protein phosphatase 1 (NIPP1) overexpression contributes to the malignant phenotype in HCC. The aim of this study was to investigate the role of NIPP1 in HCC development under hypoxia. We first conducted a study with 106 cases to explore the association of NIPP1 and/or enhancer of zeste homolog 2 (EZH2) expression with poor prognosis in HCC. Then additional 352 independent cases were recruited to validate the results in the first stage. Hypoxia was induced by culturing HCC cells in 1 % O2 or of the treatment with hypoxic agent. The expression levels of NIPP1/EZH2 in both HCC tissues and HCC cell lines were detected by RT-PCR, Western blot, or immunohistochemistry. We also studied the effects of the loss of function of NIPP1 and EZH2 on malignant phenotypes, downstream pathway, and inflammatory factors activities using gene silencing strategy. Overall, we found that NIPP1 and EZH2 were overexpressed in both HCC tissue samples and HCC cell lines. High expression of HIPP1 was associated with poor prognosis and clinicopathological features in patients with advanced HCC. HIPP1 expression positively correlated with the expression of hypoxia marker (carbonic anhydrase IX). Hypoxia induced high expression of NIPP1. NIPP1/EZH2 knockdown in HCC cell lines under hypoxia suppressed the malignant phenotypes, reduced the expression of hypoxia-inducible Factor 1α, downstream molecules of EZH2, and inhibit the activity of inflammatory factors. In conclusion, we found that NIPP1 could be activated by hypoxia and contributed to hypoxia-induced invasive and metastatic potential in HCC.
Databáze: OpenAIRE
Externí odkaz: