miR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1.

A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor, called tumor-initiating cells (TICs) or cancer stem cells (CSCs). Here we describe the identification and characterization of such cells from hepatocellular carcinoma (HCC) using the marker CD133. CD133 accounts for approximately 1.3%-13.6% of the cells in the bulk tumor of human primary HCC samples. When compared with their CD133⁻ counterparts, CD133(+) cells not only possess the preferential ability to form undifferentiated tumor spheroids in vitro but also express an enhanced level of stem cell-associated genes, have a greater ability to form tumors when implanted orthotopically in immunodeficient mice, and can be serially passaged into secondary animal recipients. Xenografts resemble the original human tumor and maintain a similar percentage of tumorigenic CD133(+) cells. Quantitative PCR analysis of 41 separate HCC tissue specimens with follow-up data found that CD133(+) tumor cells were frequently detected at low quantities in HCC, and their presence was also associated with worse overall survival and higher recurrence rates. Subsequent differential microRNA expression profiling of CD133(+) and CD133⁻ cells from human HCC clinical specimens and cell lines identified an overexpression of miR-130b in CD133(+) TICs. Functional studies on miR-130b lentiviral-transduced CD133⁻ cells demonstrated superior resistance to chemotherapeutic agents, enhanced tumorigenicity in vivo, and a greater potential for self renewal. Conversely, antagonizing miR-130b in CD133(+) TICs yielded an opposing effect. The increased miR-130b paralleled the reduced TP53INP1, a known miR-130b target. Silencing TP53INP1 in CD133⁻ cells enhanced both self renewal and tumorigenicity in vivo. Collectively, miR-130b regulates CD133(+) liver TICs, in part, via silencing TP53INP1.

Ma S ，Tang KH ，Chan YP ，Lee TK ，Kwan PS ，Castilho A ，Ng I ，Man K ，Wong N ，To KF ，Zheng BJ ，Lai PB ，Lo CM ，Chan KW ，Guan XY ... -  《-》

microRNA-150 inhibits human CD133-positive liver cancer stem cells through negative regulation of the transcription factor c-Myb.

Zhang J ，Luo N ，Luo Y ，Peng Z ，Zhang T ，Li S ... -  《-》

CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling.

A novel theory in the field of tumor biology postulates that cancer growth is driven by a population of stem-like cells, called tumor-initiating cells (TICs). We previously identified a TIC population derived from hepatocellular carcinoma (HCC) that is characterized by membrane expression of CD133. Here, we describe a novel mechanism by which these cells mediate tumor growth and angiogenesis by systematic comparison of the gene expression profiles between sorted CD133 liver subpopulations through genome-wide microarray analysis. A significantly dysregulated interleukin-8 (IL-8) signaling network was identified in CD133(+) liver TICs obtained from HCC clinical samples and cell lines. IL-8 was found to be overexpressed at both the genomic and proteomic levels in CD133(+) cells isolated from HCC cell lines or clinical samples. Functional studies found enhanced IL-8 secretion in CD133(+) liver TICs to exhibit a greater ability to self-renew, induce tumor angiogenesis, and initiate tumors. In further support of these observations, IL-8 repression in CD133(+) liver TICs by knockdown or neutralizing antibody abolished these effects. Subsequent studies of the IL-8 functional network identified neurotensin (NTS) and CXCL1 to be preferentially expressed in CD133(+) liver TICs. Addition of exogenous NTS resulted in concomitant up-regulation of IL-8 and CXCL1 with simultaneous activation of p-ERK1/2 and RAF-1, both key components of the mitogen-activated protein kinase (MAPK) pathway. Enhanced IL-8 secretion by CD133(+) liver TICs can in turn activate an IL-8-dependent feedback loop that signals through the MAPK pathway. Further, in its role as a liver TIC marker CD133 also plays a functional part in regulating tumorigenesis of liver TICs by way of regulating NTS, IL-8, CXCL1, and MAPK signaling. CD133(+) liver TICs promote angiogenesis, tumorigenesis, and self-renewal through NTS-induced activation of the IL-8 signaling cascade.

Tang KH ，Ma S ，Lee TK ，Chan YP ，Kwan PS ，Tong CM ，Ng IO ，Man K ，To KF ，Lai PB ，Lo CM ，Guan XY ，Chan KW ... -  《-》

Identification and characterization of tumorigenic liver cancer stem/progenitor cells.

Ma S ，Chan KW ，Hu L ，Lee TK ，Wo JY ，Ng IO ，Zheng BJ ，Guan XY ... -  《GASTROENTEROLOGY》

MiR-155 targets TP53INP1 to regulate liver cancer stem cell acquisition and self-renewal.

In liver cancer, miR-155 up-regulation can regulate cancer-cell invasion. However, whether miR-155 expression is associated with liver cancer stem cells (CSCs) remains unknown. Here, we show that miR-155 expression is up-regulated in tumor spheres. Knock-down of miR-155 resulted in suppression of tumor sphere formation, through a decrease in the proportion of CD90(+) and CD133(+) CSCs and in the expression of Oct4, whereas miR-155 overexpression had the opposite effect. TP53INP1 was determined to be involved in the CSCs-like properties that were regulated by miR-155. Thus, miR-155 may play an important role in promoting the generation of stem cell-like cells and their self-renewal by targeting the gene TP53INP1.

Liu F ，Kong X ，Lv L ，Gao J ... -  《-》