MicroRNA-543 suppresses colorectal cancer growth and metastasis by targeting KRAS, MTA1 and HMGA2.

miR-543 has been implicated as having a critical role in the development of breast cancer, endometrial cancer and hepatocellular carcinoma. However, the exact clinical significance and biological functions of miR-543 in colorectal cancer (CRC) remain unclear. Here, we found that miR-543 expression significantly downregulated in tumors from patients with CRC, APCMin mice and a mouse model of colitis-associated colon cancer. miR-543 level was inversely correlated with the metastatic status of patients with CRC and the metastatic potential of CRC cell lines. Moreover, ectopic expression of miR-543 inhibited the proliferation and metastasis of CRC cells in vitro and in vivo by targeting KRAS, MTA1 and HMGA2. Conversely, miR-543 knockdown promoted the proliferation, migration and invasion of CRC cells in vitro and augmented tumor growth and metastasis in vivo. Furthermore, we found that miR-543 expression was negatively correlated with the levels of KRAS, MTA1 and HMGA2 in clinical samples. Collectively, these data show that miR-543 inhibits the proliferation and metastasis of CRC cells by targeting KRAS, MTA1 and HMGA2. Our study highlights a pivotal role for miR-543 as a suppressor in the regulation of CRC growth and metastasis and suggests that miR-543 may serve as a novel diagnostic and prognostic biomarker for CRC metastasis.

Differentiation and transdifferentiation potentials of cancer stem cells.

Tumor cells actively contribute to constructing their own microenvironment during tumorigenesis and tumor progression. The tumor microenvironment contains multiple types of stromal cells that work together with the extracellular matrix and local and systemic factors to coordinately contribute to tumor initiation and progression. Tumor cells and their stromal compartments acquire many genetic and/or epigenetic alternations to facilitate tumor growth and metastasis. The cancer stem cell (CSC) concept has been widely applied to interpreting tumor initiation, growth, metastasis, dormancy and relapse. CSCs have differentiation abilities to generate the original lineage cells that are similar to their normal stem cell counterparts. Interestingly, recent evidence demonstrates that CSCs also have the potential to transdifferentiate into vascular endothelial cells and pericytes, indicating that CSCs can transdifferentiate into other lineage cells for promoting tumor growth and metastasis in some tissue contexts instead of only recruiting stromal cells from local or distant tissues. Although the transdifferentiation of CSCs into tumor stromal cells provides a new dimension that explains tumor heterogeneity, many aspects of CSC transdifferentiation remain elusive. In this review, we summarize the multi-lineage differentiation and transdifferentiation potentials of CSCs as well as discuss their potential contributions to tumor heterogeneity and tumor microenvironment in tumor progression.

MicroRNA-33b Inhibits Breast Cancer Metastasis by Targeting HMGA2, SALL4 and Twist1.

MicroRNAs are a class of small noncoding RNAs that regulate gene expression post-transcriptionally either by inhibiting protein translation or by causing the degradation of target mRNAs. Current evidence indicates that miR-33b is involved in the regulation of lipid metabolism, cholesterol homeostasis, glucose metabolism and several human diseases; however, whether miR-33b contributes to the pathogenesis of human cancers and participates in the regulation of self-renewal of human cancer stem cells remains unknown. Here, we report the identification of miR-33b as a negative regulator of cell stemness and metastasis in breast cancer. Compared with paired normal breast tissues, miR-33b expression is downregulated in breast tumor samples and is inversely correlated with lymph node metastatic status. Ectopic overexpression of miR-33b in highly metastatic breast cancer cells suppresses cell self-renewal, migration and invasion in vitro and inhibits lung metastasis in vivo. Conversely, miR-33b knockdown promotes the self-renewal, migration and invasion capabilities of noncancerous mammary epithelial cells. The mechanism through which miR-33b inhibits the stemness, migration and invasion of breast cancer cells is by targeting HMGA2, SALL4 and Twist1. These data indicate that miR-33b acts as an onco-suppressive microRNA in breast cancer progression by inhibiting the stemness and metastasis of breast cancer cells.

Periostin, a multifunctional matricellular protein in inflammatory and tumor microenvironments.

The behavior and fate of cells in tissues largely rely upon their cross-talk with the tissue microenvironment including neighboring cells, the extracellular matrix (ECM), and soluble cues from the local and systemic environments. Dysregulation of tissue microenvironment can drive various inflammatory diseases and tumors. The ECM is a crucial component of tissue microenvironment. ECM proteins can not only modulate tissue microenvironment but also regulate the behavior of surrounding cells and the homeostasis of tissues. As a nonstructural ECM protein, periostin is generally present at low levels in most adult tissues; however, periostin is often highly expressed at sites of injury or inflammation and in tumors within adult organisms. Current evidence demonstrates that periostin actively contributes to tissue injury, inflammation, fibrosis and tumor progression. Here, we summarize the roles of periostin in inflammatory and tumor microenvironments.

Twist2 promotes self-renewal of liver cancer stem-like cells by regulating CD24.

Twist2 is a highly conserved basic helix-loop-helix transcription factor that plays a critical role in embryogenesis. Recent evidence has revealed that aberrant Twist2 expression contributes to tumor progression; however, the role of Twist2 in human hepatocellular carcinoma (HCC) and its underlying mechanisms remain undefined. In this report, we demonstrate that Twist2 is overexpressed in human HCC tumors. We show that ectopic expression of Twist2 induces epithelial-mesenchymal transition phenotypes, augments cell migration and invasion and colony-forming abilities in human HCC cells in vitro, and promotes tumor growth in vivo. Moreover, we found a higher percentage of CD24(+) liver cancer stem-like cells in Twist2-transduced HCC cells. Twist2-expressing cells exhibited an increased expression of stem cell markers Bmi-1, Sox2, CD24 and Nanog and an increased capacity for self-renewal. Knockdown of CD24 in HepG2/Twist2 cells decreased the levels of Sox2, pSTAT3 and Nanog, and reversed the cancer stem-like cell phenotypes induced by ectopic expression of Twist2. Furthermore, Twist2 regulated the CD24 expression by directly binding to the E-box region in CD24 promoter. Therefore, our data demonstrated that Twist2 augments liver cancer stem-like cell self-renewal in a CD24-dependent manner. Twist2-CD24-STAT3-Nanog pathway may play a critical role in regulating liver cancer stem-like cell self-renewal. The identification of the Twist2-CD24 signaling pathway provides a potential therapeutic approach to target cancer stem cells in HCCs.

Tumor angiogenesis: a new source of pericytes.

Glioblastoma stem cells have been reported to directly contribute to the tumor vasculature by endothelial cell differentiation. Interestingly, a recent study demonstrates that glioblastoma stem cells preferentially differentiate into vascular pericytes to support vasculature function and tumor growth.