Abstract 4275: BMI-1 promotes drug resistance and cellular invasion in head and neck cancer stem cells

Abstract

Abstract Recently, the growth and metastasis of tumors, including head and neck squamous cell carcinomas (HNSCC), have been attributed to a subpopulation within tumors known as cancer stem cells (CSC). Studies have shown that HNSCC cells that are CD44+ are putative CSC and have the capability to self-renew, differentiate and preferentially express BMI-1. The polycomb group protein BMI-1 is a transcriptional repressor that silences the genes responsible for the expression of the cell cycle inhibitor genes p16 and p19. The gene is essential for maintaining the self-renewal capability of both normal and CSC. Very recent studies have shown that BMI-1 may also be implicated in other critical roles in cancer cell behavior including its role in the invasiveness of cancer cells. In this study, we demonstrate that in HNSCC CSC, BMI-1 is critical for cellular invasion. Knockdown of BMI-1 in CD44+ cells results in significant inhibition of invasion while overexpression of BMI-1 in CD44- cells promotes invasion. Furthermore, we show that this enhaced invasion conferred by BMI-1 is through induction of epithelial-to-mesenchymal transition (EMT) genes and the down-regulation of E-cadherin. In addition, we present evidence that the proteinases MMP2 and MMP9 are induced upon overexpression of BMI-1. CSC are also characterized by being chemoresistant, in part through their enhanced ability to extrude drugs because of their high expression of drug transporters. In this study, we demonstrate another mechanism for the resistance of CSC to DNA-damaging agents. We present evidence that another function of BMI-1 in CSC is its ability to regulate apoptosis. Knockdown of BMI1-1 in CSC using siRNA resulted in increased levels of cisplatin-induced apoptosis compared to cells transfected with scrambled siRNA. Our findings lend support to previous studies that have implicated BMI-1 in the regulation of pro-survival genes as well as the DNA damage response pathway. Our findings have revealed that BMI-1 is not only essential for self-renewal and tumorigenesis, but also that it has critical functions in cancer stem cell drug resistance and invasion, and most likely, metastasis. Since BMI-1 controls many of the properties of CSC and is preferentially expressed in HNSCC CSC, this oncogene may serve not only as a tumor marker, but also as an ideal therapeutic target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4275.