Role of the Hypoxia-inducible factor-1 alpha induced autophagy in the conversion of non-stem pancreatic cancer cells into CD133+ pancreatic cancer stem-like cells

Haitao Zhu,Zhaoliang Su,Yingying Wu,Dongqing Wang,Yuepeng Zhou,Ming Yu,Zhijian Zhang,Lirong Zhang,Genbao Shao,Fangfang Chen,Yanfang Liu

doi:10.1186/1475-2867-13-119

Abstract

The initiation and progression of various solid tumors, including pancreatic carcinoma, are driven by a population of cells with stem cell properties, namely cancer stem cells (CSCs). Like their normal counterparts, CSCs are also believed to rely on their own microenvironment termed niches to sustain the population. Hypoxia-inducible factor-1α (HIF-1α) is a major actor in the cell survival response to hypoxia. Recently, several researchers proposed that non-stem cancer cells can convert to stem-like cells to maintain equilibrium. The present study focuses on whether non-stem pancreatic cancer cells can convert to stem-like cells and the role of HIF-1α and autophagy in modulating this conversation. The non-stem pancreatic cancer cells and pancreatic cancer stem-like cells were separated by magnetic sorting column. Intermittent hypoxia enhanced stem-like properties of non-stem pancreatic cancer cells and stimulated the levels of HIF-1α, LC3-II and Beclin. Enhanced autophagy was associated with the elevated level of HIF-1α. The conversation of non-stem pancreatic cancer cells into pancreatic cancer stem-like cells was induced by HIF-1α and autophagy. This novel finding may indicate the specific role of HIF-1α and autophagy in promoting the dynamic equilibrium between CSCs and non-CSCs. Also, it emphasizes the importance of developing therapeutic strategies targeting cancer stem cells as well as the microenvironmental influence on the tumor.

Highlights

Pancreatic cancer is the fourth leading cause of cancerrelated death in the United States
The mRNA and protein levels of Oct-4 and c-MYC were significantly increased in Cluster of differentiation 133 (CD133)+ pancreatic cancer stem-like cells compared to CD133- nonstem pancreatic cancer cells (Figure 1B and C)
We determine whether intermittent hypoxia increase the expression of stem cell associated proteins in the bulk pancreatic cells which referred to the total cells without sorting by the magnetic sorting column using RT-Polymerase chain reaction (PCR) and Western-blot assay

Summary

Introduction

Pancreatic cancer is the fourth leading cause of cancerrelated death in the United States. It is characterized by rapid progression, early metastasis, and a limited response to chemotherapy [1]. A distinct population of cancer cells, namely cancer stem cells, had been defined and characterized in several human cancers, including pancreatic cancer [4,5,6]. Most described CSCs were isolated from solid tumors based on the expression of surface markers [7,8]. CD133 is a marker protein typically used to identify and isolate human pancreatic CSCs [9]. Due to failing to eradicate the CSCs population, traditional cancer therapies are effective at reducing tumor mass but often fail to produce long-term clinical complete remissions. A number of studies in recent years have demonstrated that CSCs are located in specialized microenvironments within tumor [11,12,13]

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