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Fig. 1. Transcription factors that regulate
PROM1 gene expression. (A) Reported tran-scription factors positively regulate PROM1 gene expression. P1-P5 are the promoter re-gions of PROM1. (B) Transcription factor p53 represses PROM1 gene expression by recruiting histone deacetylase 1 (HDAC1) that removes acetyl groups from lysine residues of the chromosome. Deacetylation of lysines in-creases the binding between the histones and DNA, thus preventing transcription of PROM1. NICD: intracellular domain of Notch; HIF: hy-poxia inducing factor; IL-6: interleukin 6; the dashed line of a flag: deacetylated lysine.
types of Brefeldin A (Hemmati et al., 2003; Singh et al., 2003, 2004; Yin et al., 1997), known as stem cell properties, CD133+ cancer cells are cancer stem cells (CSCs). In addition to CD133, other general cancer stem cell markers include CD44 and aldehyde dehydrogenase1A1 (ALDH1A1). Heterogeneous populations of the CSCs are present among diﬀerent types of cancer according to their protein expression profiles. For ex-ample, pancreatic cancer stem cells express high levels of CD133, CD44, CD24, epithelial-specific antigen (ESA), ALDH1A1, CXCR4, DCLK-1 and BMI-1, while lung cancer stem cells have increased expression of ALDH1A1, ABCG2, CD90, CD117 and epithelial cellular adhesion mo-lecule (EpCAM) (Hardavella et al., 2016; Proctor et al., 2013; Rao and Mohammed, 2015; Wang et al., 2014).
The CD133 expression is regulated by Notch, p53, hypoxia-inducing factor (HIF) and signal transducer and activator of transcription 3 (STAT3) in cancer (Fig. 1). It has been demonstrated that the in-tracellular domain of Notch 1 directly bound to the RBP-Jκ site of the 5′ promoter region of PROM1 to regulate CD133 transcription (Konishi et al., 2016). Knockdown of Notch1 or treatment of Notch inhibitors decreased CD133 expression in cultured gastric cancer and melanoma cells (Konishi et al., 2016; Kumar et al., 2016). There are 5 diﬀerent promoters, including promoter 1 (P1) to promoter 5 (P5) in the 5´ untranslated region of CD133 for alternatively splicing variants. HIF increased the promoter activity of PROM1 through its direct binding to the P5 region of PROM1 where it interacted with ETS transcription factors such as Elk1 (Ohnishi et al., 2013). Recently, it has been re-ported that STAT3 activated by IL-6 can turn on the PROM1 gene through upregulation of HIF transcription in liver cancer cells (Won et al., 2015). In human lung cancer cells cultured at a hypoxia condi-tion, binding of OCT4 and SOX2 to the P1 region of PROM1 was re-quired for HIF-induced CD133 expression (Iida et al., 2012), revealing another mechanism that HIF modulates CD133 expression in addition to the P5 region of PROM1. Transcription factor p53 negatively reg-ulates mRNA and protein levels of CD133 by directly binding to the P5 region of PROM1, and subsequent recruitment and activation of histone deacetylase 1 (HDAC1) (Park et al., 2015). Activation of HDAC1 re-moved the acetyl groups from lysine residues of the chromosome, and subsequently increased the binding between the histones and DNA, thus preventing transcription of PROM1. r> This review provides the current updates on how CD133 regulates diﬀerent stages of cancer development, including initiation, progression and advancement (metastasis) especially through transcription factors and cell signaling. In addition, recent findings on the mechanisms that CD133 utilizes to enhance cancer cells resistances to therapeutic treatments are also summarized for oﬀering some insights into a po-tential modulation on CD133 and its mediated signaling for a ther-apeutic development purpose.
Cancer-initiating cells possess tumor-initiating capacity which is one of the characteristics of CSCs. CSCs are believed to be a major source of cancer-initiating cells during cancer onset. A major body of evidence has demonstrated that the isolated CD133+ cancer cells from patients are capable of forming cancers in immune-comprised xenograft mice, implicating the involvement of CSCs in cancer initiation. When using the renal capsule transplantation in immunodeficient mice to identify human colon cancer initiating cells, only CD133+ colon cancer cells can initiate tumor growth in vivo, but not CD133− colon cancer cells (O’brien et al., 2007). It suggested that CD133+ colon cancer cells are the colon cancer initiating cells. Furthermore, colon cancer-in-itiating cells are enriched in CD133+ cancer cells than in all colon cancer cells. Similarly, using an in vivo serial transplantation of human ovarian tumors into immunocompromised mice to identify ovarian tumor-initiating cells, CD133 was revealed as an ovarian CSC marker (Curley et al., 2009). In addition to recapitulating the parental het-erogeneous cancer phenotype, the isolated CD133+ ovarian tumor cells have a higher tumor-forming ability in vivo as compared to the CD133− ovarian tumor cells.