HMGA1 silencing restores normal stem cell characteristics in colon cancer stem cells by increasing p53 levels.

Francesca Puca,Marica Gemei,Luigi Del Vecchio,Salvatore Pece,Nadia Tosti,André Uchimura Bastos,Sabrina Battista,Marianna Colamaio,Alfredo Fusco,Antonella Federico

doi:10.18632/oncotarget.1914

Abstract

High-mobility group A1 (HMGA1) proteins are architectural chromatinic proteins, abundantly expressed during embryogenesis and in most cancer tissues, but expressed at low levels or absent in normal adult tissues. Several studies have demonstrated that HMGA1 proteins play a causal role in neoplastic cell transformation. The aim of this study was to investigate the role of these proteins in the control of cancer stem cells (CSCs), which have emerged as a preferred target in cancer therapy, because of their role in cancer recurrence. We observed that HMGA1 is overexpressed in colon tumour stem cell (CTSC) lines compared to normal and colon cancer tissues. We demonstrated that HMGA1 silencing in CTSCs increases stem cell quiescence and reduces self-renewal and sphere-forming efficiency (SFE). The latter, together with the upregulation and asymmetric distribution of NUMB, is indicative of the recovery of an asymmetric division pattern, typical of normal stem cells. We further found that HMGA1 transcriptionally regulates p53, which is known to control the balance between symmetric and asymmetric divisions in CSCs. Therefore, our data indicate a critical role for HMGA1 in regulating both self-renewal and the symmetric/asymmetric division ratio in CSCs, suggesting that blocking HMGA1 function may be an effective anti-cancer therapy.

Highlights

Cancer arises from a small set of stem cells, or tumour-initiating cells, that differ from normal stem cells in their deregulated self-renewal and differentiation programs [1]
High-mobility group A1 (HMGA1) is overexpressed in colon tumour stem cell (CTSC) and in the CD133+ sub-population
When CTSCs were stained for the cancer stem cell marker CD133 and sorted, HMGA1 expression was enriched in CD133+ cells (Figure 1B)

Summary

Introduction

Cancer arises from a small set of stem cells, or tumour-initiating cells, that differ from normal stem cells in their deregulated self-renewal and differentiation programs [1]. The cancer typically returns with even more aggressive characteristics due to a few tumour-founding cells (the cancer stem cells or CSCs), which, because of their intrinsic chemoresistance, are spared and “naturally selected” by the routinely used anticancer drugs This common trend makes the identification of CSC-specific targets and tightly related CSC-specific drugs necessary for the development of new effective anticancer therapies. The levels of HMGA proteins are low or absent in normal cells and adult tissues but are elevated in many tumours, neoplastically transformed cells, and embryonic cells [4]. Their overexpression is largely associated with a highly malignant phenotype and represents a poor prognostic marker, as HMGA overexpression often correlates with the presence of metastasis and reduced survival [5]. Transgenic mice overexpressing either HMGA1 or HMGA2 develop uterine tumours, haematopoietic tumours, and pituitary adenomas [8,9,10,11]

Objectives

Methods

Results

Conclusion