Abstract
Gallbladder cancer (GBC) is a malignant cancer with very poor prognosis. Although promyelocytic leukemia zinc-finger protein (PLZF) was reported to be deregulated in numerous cancers and also relevant to clinical prognosis, its role in GBC progression has been little known. In this study, we found PLZF expression was decreased in GBC, correlating to advanced TNM stage, distant metastasis, and shorter overall survival. Moreover, ectopic PLZF expression in GBC cells (NOZ and GBC-SD) significantly reduced the cell proliferation, migration, and invasion. Consistently, overexpression of PLZF in xenograft mice model could suppress tumor growth and liver metastasis. Mechanical investigations verified PLZF could regulate the expression of cell cycle arrest-associated gene p21 and epithelial–mesenchymal transition (EMT)-related genes (E-cadherin and N-cadherin) in GBC cell lines. Importantly, PLZF remarkably increased the mRNA transcription of interferon-induced protein with tetratricopeptide repeat 2 (IFIT2) by increasing STAT1 protein level, a known factor involved in tumor progression. Furthermore, ablation of IFIT2 in PLZF overexpression cells abrogated the tumor-suppressive function of PLZF, at least partially, leading to impaired tumor growth and EMT program. These studies indicated PLZF inhibited the proliferation and metastasis via regulation of IFIT2. In conclusion, our study demonstrated PLZF could be a promising tumor biomarker for GBC, and also be a potential therapeutic target.
Highlights
Gallbladder cancer (GBC) is a highly lethal and the most common biliary tract cancer, ranking the sixth leading cause of cancer-related death of digestive system[1,2]
To further investigate the clinical significance of PLZF expression in GBC, we evaluated the correlation between PLZF expression and the clinicopathological characteristics through statistical analysis
GBC is a malignant cancer with very poor prognosis because of its high potential to metastasize in a short time[21]
Summary
Gallbladder cancer (GBC) is a highly lethal and the most common biliary tract cancer, ranking the sixth leading cause of cancer-related death of digestive system[1,2]. Given the lack of specific tumor marker and effective therapeutic targets for GBC, novel insight into the GBC progression contributes to the identification of potential targets for early diagnosis and therapy. The role of PLZF appeared to be controversial in tumor progression. Several studies showed PLZF was able to reduce cell growth and survival in numerous cancers including melanoma, malignant mesothelioma, prostate cancer, and non-small cell lung cancer cells via c-myc suppression or poly ADP-ribose polymerase (PARP) and Mcl-1 expression increase[8,9,10,11,12,13]
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