POU2F1 over-expression correlates with poor prognoses and promotes cell growth and epithelial-to-mesenchymal transition in hepatocellular carcinoma.

Qingxia Wu,Min Chen,Hongyang Huang,Yonghao Zhong,Guang-Rong Yan,De Chen,Jinzhou Huang

doi:10.18632/oncotarget.17296

Qingxia Wu, Min Chen + Show 5 more

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https://doi.org/10.18632/oncotarget.17296

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Abstract

Despite recent efforts to understand activities of POU domain class 2 transcription factor 1 (POU2F1), little is known about the roles of POU2F1 in hepatocellular carcinoma (HCC) tumorigenesis and its correlation with any clinicopathological feature of HCC. In this study, we found that POU2F1 was significantly up-regulated in HCC specimens compared with adjacent non-cancerous liver specimens. The high POU2F1 protein expression level positively correlated with large tumor size, high histological grade, tumor metastasis and advanced clinical stage, and HCC patients with high POU2F1 levels exhibited poor prognoses. We further demonstrated that POU2F1 over-expression promoted HCC cell proliferation, colony formation, epithelial-to-mesenchymal transition (EMT), migration and invasion, while silencing of POU2F1 inhibited these malignant phenotypes. POU2F1 induced the expression of Twist1, Snai1, Snai2 and ZEB1 genes which are involved in the regulation of EMT. Furthermore, POU2F1 was up-regulated by AKT pathway in HCC, and POU2F1 over-expression reversed the inhibition of malignant phenotypes induced by AKT knock-down, indicating POU2F1 is a key down-stream effector of AKT pathway. Collectively, our results indicate that POU2F1 over-expression is positively associated with aggressive phenotypes and poor survival in patients with HCC, and POU2F1 regulated by AKT pathway promotes HCC aggressive phenotypes by regulating the transcription of EMT genes. POU2F1 may be employed as a new prognostic factor and therapeutic target for HCC.

Highlights

Hepatocellular carcinoma (HCC), the sixth most prevalent type of cancer, is the fourth leading cause of cancer-related morbidity and mortality in China [1, 2]
Analyses of databases revealed that POU domain class 2 transcription factor 1 (POU2F1) showed higher expression levels in kidney, ovary, and esophageal cancer, which was compared to normal controls, whereas expression of POU2F1 in some brain tumors, bladder cancer, and liposarcoma was reduced [18]
Another study which focused on intestinaltype gastric cancer showed that 74% of the 42 gastric carcinoma samples displayed an increasing POU2F1 protein level, respectively [19]

Summary

INTRODUCTION

Hepatocellular carcinoma (HCC), the sixth most prevalent type of cancer, is the fourth leading cause of cancer-related morbidity and mortality in China [1, 2]. It is a ubiquitous transcription factor that regulates www.impactjournals.com/oncotarget the transcription of target genes associated with cell cycles [7]. POU2F1 is involved in the cell differentiation through regulation of housekeeping genes like H2B and snRNAs, and it participates in immunity and inflammation via modulation of tissue-specific target gene expression [8, 9]. It was reported to be over-expressed in osteosarcoma tumors and identified as an independent prognostic factor in gastric carcinoma [12, 13]. We reported that expression of POU2F1 was increased in HCC tissues compared with adjacent non-cancerous liver specimens, and this alteration in POU2F1 was observed in HCC patients with metastasis compared to non- metastasis. POU2F1 over-expression was associated with a worse outcome of patients with HCC. This study indicates the functional roles of POU2F1 in the development and progression of HCC

RESULTS

DISCUSSION

MATERIALS AND METHODS