第3卷，第1期

1306

Tumour heterogeneity is a phenomenon where each cell that makes up a tumour, contains mutations that differ from that of other cells in the tumour. The clonal evolution and cancer stem cell theories of cancer formation, have been used to explain tumour heterogeneity. The theories both point to the existence of cells within a tumour that are capable of initiating the tumour in a different location. While the clonal evolution theory argues that all cells within a tumour possess this ability, the cancer stem cell theory argues that only a few cells (cancer stem cells or CSCs) within the tumour possess this ability to seed the tumour in a different location. Data supporting the cancer stem cell theory is accumulating. Researchers have targeted these CSCs therapeutically, hypothesizing that since these CSCs are the 'drivers' of tumour progression, their death may inhibit tumour progression. This was foiled by tumour cell plasticity, a phenomenon whereby a non-CSC spontaneously de-differentiates into a CSC. Researchers are now working on combinations that kill both CSCs and non-CSCs as well as drugs that prevent non-CSC-to-CSC transition. This review concisely describes CSCs and how they contribute to the difficulty in treating cancer.

1249

Wnt signaling transduces evolutionarily conserved pathways which play important roles in initiating and regulating a diverse range of cellular activities, including cell proliferation, calcium homeostasis, and cell polarity. The role of Wnt signaling in controlling cell proliferation and stem cell self-renewal is primarily carried out through the canonical pathway, which is the best-characterized the multiple Wnt signaling branches. The past 10 years has seen a rapid expansion in our understanding of the complexity of this pathway, as many new components of Wnt signaling have been identified and linked to signaling regulation, stem cell functions, and adult tissue homeostasis. Additionally, a substantial body of evidence links Wnt signaling to tumorigenesis of cancer types and implicates it in the development of cancer drug resistance. Thus, a better understanding of the mechanisms by which dysregulation of Wnt signaling precedes the development and progression of human cancer may hasten the development of pathway inhibitors to augment current therapy. This review summarizes and synthesizes our current knowledge of the canonical Wnt pathway in development and disease. We begin with an overview of the components of the canonical Wnt signaling pathway and delve into the role this pathway has been shown to play in stemness, tumorigenesis, and cancer drug resistance. Ultimately, we hope to present an organized collection of evidence implicating Wnt signaling in tumorigenesis and chemoresistance to facilitate the pursuit of Wnt pathway modulators that may improve outcomes of cancers in which Wnt signaling contributes to aggressive disease and/or treatment resistance.

1328

Epithelial-mesenchymal transition (EMT) is the phenotypic transition of epithelial cells to mesenchymal cells characterized by loss of epithelial markers, loss of intercellular adherence and acquirement of mesenchymal cell markers and increased locomotive ability. EMT is widely considered to be a gene regulated process necessary for cancer metastasis. Yet it is a highly controversial issue. We here propose that EMT is an environmentally induced cell behavior. It is the mimicry of their living environment. It is a survival strategy, a way of immune escape. We also propose here that the epithelial cell markers may functionally act as tumor antigens since in the mesenchymal surroundings there are no other structures bearing the same antigens as epithelial cells.

1838

Hypoxia-inducible factor (HIF) is a main heterodimeric transcription factor that regulates the cellular adaptive response to hypoxia by stimulating the transcription of a series of hypoxia-inducible genes. HIF is frequently upregulated in solid tumors, and the overexpression of HIF can promote tumor progression or aggressiveness by blood vessel architecture and altering cellular metabolism. In this review, we focused on the pivotal role of HIF in tumor angiogenesis and energy metabolism. Furthermore, we also emphasized the possibility of HIF pathway as a potential therapeutic target in cancer.

1202

Cancer is one of the most serious diseases that cause an enormous number of deaths all over the world. Tumor metabolism has great discrimination from that of normal tissues. Exploring the tumor metabolism may be one of the best ways to find biomarkers for cancer detection, diagnosis and to provide novel insights into internal physiological state where subtle changes may happen in metabolite concentrations. Nuclear Magnetic Resonance (NMR) technique nowadays is a popular tool to analyze cell extracts, tissues and biological fluids, etc, since it is a relatively fast and an accurate technique to supply abundant biochemical information at molecular levels for tumor research. In this review, approaches in tumor metabolism are discussed, including sample collection, data profiling and multivariate data analysis methods etc. Some typical applications of NMR are also summarized in tumor metabolism.

1932

F_oF₁-ATPase is an active rotary motor, and generates three-ATP for each rotation. At saturated substrate concentration, the motor can achieve about 10³r.p.m, which means one motor can generate about 10⁵ATP molecules during 30 min. Here, we constituted a novel nanodevice with a molecular rotary motor and a "battery", F_oF₁-ATPase and chromatophore, and presented a novel method of sandwich type rotary biosensor based on ε subunit with one target-to-one motor, in which one target corresponds 10⁵ATP molecules as detection signals during 30 min. The target such as NT-proBNP detection demonstrated that this novel nanodevice has potential to be developed into an ultrasensitive biosensor to detect low expressed targets.

1921

Many cancers have similar aberrations in various signaling cascades with crucial roles in cellular proliferation, differentiation, and morphogenesis. Dysregulation of signal cascades that play integral roles during early cellular development is well known to be a central feature of many malignancies. One such signaling cascade is the Wnt/β-catenin pathway, which has a profound effect on stem cell proliferation, migration, and differentiation. This pathway is dysregulated in numerous cell types, underscoring its global oncogenetic potential. This review highlights regulators and downstream effectors of this receptor cascade and ad-dresses the increasingly apparent crosstalk of Wnt with other tumorigenic signaling pathways. As understanding of the genetic and epigenetic changes unique to these malignancies increases, identifying the regulatory mechanisms unique to the Wnt/β-catenin pathway and similarly aberrant receptor pathways will be imperative.

1210

Precise and dynamic regulation of gene expression is a key feature of immunity. In recent years, rapid advances in transcriptome profiling analysis have led to recognize long noncoding RNAs (lncRNAs) as an additional layer of gene regulation context. In the immune system, lncRNAs are found to be widely expressed in immune cells including monocytes, macrophages, dendritic cells (DC), neutrophils, T cells and B cells during their development, differentiation and activation. However, the functional importance of immune-related lncRNAs is just emerging to be characterized. In this review, we discuss the up-to-date knowledge of lncRNAs in immune regulation.

1281

Autophagy is a cellular self-eating process essential for stress response and maintaining tissue homeostasis by lysosomal degradation of unwanted or damaged proteins and or-ganelles. Here, we show that cells with defective mitochondria induce autophagy to promote cell survival through activating the AMPK pathway. Loss of mitochondrial complex III protein cytochrome b activates the AMPK signaling and induced autophagy. Inhibiting mitochondria energetics by mitochondria-targeted agents activates the AMPK signaling and induced autophagy. Genetic inhibition of AMPK inhibits autophagy induction in cells with defective mitochondria, while genetic inhibition of autophagy has no effect on AMPK activation. Mitochondria dysfunction has no effect of DNA repair of UV-induced DNA damage. However, mitochondria dysfunction sensitizes cells to apoptosis induced by UV radiation. Genetic inhibition of autophagy or AMPK sensitized cells to apoptosis in cells with defective mitochondria. Our results demonstrate that AMPK and autophagy senses mitochondria dysfunction and serves as a mechanism for survival. Our findings may provide new insights into the interplay between mitochondria function and autophagy process in maintaining tissue homeostasis, and suggest that this interaction may play important roles in diseases such as cancer and neurodegeneration.

1570

The bHLH transcription factor Twist1 has emerged as a negative regulator of chon-drogenesis in skeletal progenitor cells and as an inhibitor of maturation in growth plate chon-drocytes. However, its role in articular cartilage remains obscure. Here we examine Twist1 expression during re-differentiation of expanded human articular chondrocytes, the distribution of Twist1 proteins in normal versus OA human articular cartilage, and its role in modulating OA development in mice. High levels of Twist1 transcripts were detected by qPCR analyses of expanded de-differentiated human articular chondrocytes that had acquired mesenchymal-like features. The induction of hallmark cartilage genes by Bmp-2 mediated chondrogenic differentiation was paralleled by the dramatic suppression of Twist1 in vitro. In normal human articular cartilage, Twist1-expressing chondrocytes were most abundant in the superficial zone with little to no expression in the middle and deep zones. However, our analyses revealed a higher proportion of deep zone articular chondrocytes expressing Twist1 in human OA cartilage as compared to normal articular cartilage. Moreover, Twist1 expression was prominent within proliferative cell clusters near fissure sites in more severely affected OA samples. To assess the role of Twist1 in OA pathophysiology, we subjected wild type mice and transgenic mice with gain of Twist1 function in cartilage to surgical destabilization of the medial meniscus. At 12 weeks post-surgery, micro-CT and histological analyses revealed attenuation of the OA phenotype in Twist1 transgenic mice compared to wild type mice. Collectively, the data reveal a role for Twist in articular cartilage maintenance and the attenuation of cartilage degeneration.

1295