Dysregulation of Bmi1 promotes malignant transformation of hepatic progenitor cells.

R Zhang,C Liu,L B Xu,X D Shi,H Zeng,M S Zhu,W R Wu

doi:10.1038/oncsis.2016.6

R Zhang, C Liu + Show 5 more

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https://doi.org/10.1038/oncsis.2016.6

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Abstract

Adult hepatic progenitor cells (HPCs) are involved in a wide range of human liver diseases, including hepatocellular carcinoma (HCC). Bmi1 has been reported to have vital roles in stem cell self-renewal and carcinogenesis. We have previously demonstrated that Bmi1 is upregulated in HCC with bile duct tumor thrombi, a subtype of HCC characterized by profuse expression of hepatic stem cell markers. However, the function of Bmi1 in HPCs has not yet been well elucidated. The current study was designed to investigate the effects of Bmi1 on the biological properties of rat HPCs. To accomplish this, Bmi1 was silenced or enhanced in two HPC cell lines (WB-F344 and OC3) by, respectively, using either small interfering RNA against Bmi1 or a forced Bmi1 expression retroviral vector. The biological functions of Bmi1 in HPCs were investigated through cell proliferation assays, colony-formation assays, cell cycle analysis and invasion assays, as well as through xenograft-formation assays. In this study, genetic depletion of Bmi1 repressed cell proliferation, colony formation and invasion in both assessed HPC cell lines relative to controls. Conversely, forced expression of Bmi1 in two HPCs cell lines promoted cell proliferation, colony formation and invasion in vitro. Aldehyde dehydrogenase (ALDH) assay revealed a significant increase in the number of ALDH-positive cells following the forced expression of Bmi1 in HPCs. Most importantly, transplantation of forced Bmi1 expression HPCs into nude mice resulted in the formation of tumors with histological features of poorly differentiated HCC. Taken together, our findings indicate that forced expression of Bmi1 promotes the malignant transformation of HPCs, suggesting Bmi1 might be a potential molecular target for the treatment of HCC.

Highlights

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is the third most frequent cause of cancer-related death worldwide.[1]
It is well known that HCC mainly occurs in adulthood, but it remains unclear whether HCC can originate from the malignant transformation of adult hepatic progenitor cells (HPCs)
The results indicated that Bmi1siRNA treatment led to decreased levels of H2AK119ub in HPCs (Figure 1b)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is the third most frequent cause of cancer-related death worldwide.[1] Stem cells are a minor cell population that possesses the capability for extensive self-renewal, differentiation and the repair of damaged tissues.[2] With regard to HCC or intrahepatic cholangiocarcinoma, the carcinogenesis process has been suggested to begin with 'oval cells', which have bipotent differentiation capability and can transform into either hepatocytes or cholangiocytes This process is known as 'stem cell hit theory', a hypothesis that stem/progenitor cells in normal tissue are a source of cancer.[3] In clinical pathology, combined HCC and cholangiocarcinoma, which exhibits intermediate properties between liver and biliary tract cancer, is known to exist. It is well known that HCC mainly occurs in adulthood, but it remains unclear whether HCC can originate from the malignant transformation of adult hepatic progenitor cells (HPCs)

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