Role of SATB2 in human pancreatic cancer: Implications in transformation and a promising biomarker.

Wei Yu,Yiming Ma,Sharmila Shankar,Rakesh K Srivastava

doi:10.18632/oncotarget.10860

Abstract

SATB2 (special AT-rich binding protein-2), a transcription factor and chromatin modulator, regulates the expression of genes required for maintaining pluripotency and self-renewal. The molecular mechanisms by which human pancreatic normal ductal epithelial cells are transformed to cancer cells are not well understood. The main goal of the paper is to examine the molecular mechanisms by which SATB2 regulates transformation of human pancreatic normal ductal epithelial (HPNE) cells, and assess whether transformed HPNE cells gained the phenotypes of cancer stem cells (CSCs). The results demonstrate that SATB2 is highly expressed in pancreatic CSCs, primary tissues and cell lines, but not in HPNE cells. SATB2 induces cellular transformation, stemness and epithelial to mesenchymal transition in HPNE cells, and inhibition of its expression suppresses these activities. Overexpression of SATB2 in HPNE cells resulted in induction of stem cell markers (CD44, CD24 and CD133), and transcription factors (Oct4, Sox2 and Nanog). SATB2 can directly bind to promoters of Bcl-2, Bsp, Nanog, c-Myc, XIAP, Klf4 and Hoxa2, suggesting the role of SATB2 in pluripotency, cell survival and proliferation. SATB2-overexpressing HPNE cells (HPNE/SATB2) formed tumors in Balb C nude mice, whereas HPNE/Empty vector cells did not form any tumor. Since SATB2 is highly expressed in human pancreatic cancer tissues and cell lines, but not in HPNE cells and normal pancreatic tissue, it can drive pancreatic cancer growth and metastasis. Our findings suggest that SATB2 can induce dedifferentiation by inducing stemness and may have a role in pancreatic carcinogenesis, and can be used as a diagnostic biomarker.

Highlights

Pancreatic cancer is one of the leading causes of cancer-related deaths in the Western world, and its incidences are increasing [1]
SATB2 is highly expressed in pancreatic cancer stem cells (CSCs) and cell lines, but not in human pancreatic normal ductal epithelial (HPNE) cells
In order to understand the biological function of SATB2, we first compared its expression in HPNE cells, pancreatic cancer cell lines (AsPC-1, BxPC-3, Mia-PaCa-2, and PANC-1) and Pan CSCs by Western blot analysis and qRT-PCR

Summary

Introduction

Pancreatic cancer is one of the leading causes of cancer-related deaths in the Western world, and its incidences are increasing [1]. At the time of diagnosis many pancreatic cancers are not resectable due to metastasis to the regional lymph nodes and distant organs, and these characteristics make the management of pancreatic cancer very difficult [3]. Our recent studies showed the existence of CSCs in pancreatic tissues isolated from human and KrasG12D mice [5,6,7,8]. These cells were similar to normal stem cells and expressed cell surface markers such as CD24, CD44, ESA and CD133 [2]. Pancreatic CSCs isolated from human primary tumors and KrasG12D mice are tumorigenic, the molecular mechanisms by which human pancreatic normal ductal epithelial (HPNE) cells are transformed to malignant phenotype are not well understood

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