TCF4 promotes colorectal cancer drug resistance and stemness via regulating ZEB1/ZEB2 expression

The present study aims to investigate the roles of TCF4 and its underlying mechanism in colorectal cancer (CRC). Doxorubicin-resistant DLD-1 (DLD1 DR), TCF4 overexpression, and TCF4 knockdown cell lines were constructed. A flow cytometer was used to analyze frequencies of CD133+ cell in the DLD1 and DLD1 DR cells. Quantitative real-time PCR (qPCR) was used to determine the expressions of cancer stem cell (CSC) makers. Stemness of CRC cells were determined using tumorsphere formation assay. The correlation between TCF4 and ZEB1/ZEB2 were determined using public data from The Cancer Genome Atlas (TCGA) datasets. ZEB1/ZEB2 overexpression cell lines were constructed and cell viabilities were then determined using MTT and colony formation assays. TCF4 overexpression promoted proliferation of CRC cell lines and relative expressions of TCF4 were significantly increased in the DLD1 DR cells. TCF4 overexpression promoted CRC cell doxorubicin resistance, whereas TCF4 knockdown significantly decreased doxorubicin resistance. Additionally, TCF4 overexpression also significantly increased frequencies of CSC cells, expressions of CSC markers, and CRC ability to form tumorsphere. Furthermore, TCF4 promoted ZEB1 and ZEB2 expression, leading to CRC proliferation and doxorubicin resistance. TCF4 promoted CRC doxorubicin resistance and stemness by regulating expressions of ZEB1 and ZEB2.     

Epithelial–mesenchymal transition in cancer metastasis: Mechanisms,markers and strategies to overcome drug resistance in the clinic

Epithelial–mesenchymal transition (EMT) is a key step during embryogenesis. Accumulating evidence suggests a critical role in cancer progression, through which tissue epithelial cancers invade and metastasise. Cell characteristics are highly affected during EMT, resulting in altered cell–cell and cell–matrix interactions, cell motility and invasiveness. Nevertheless, the demonstration of this process in human cancer has been proven difficult and controversial. Besides the fact that the acquisition of mesenchymal characteristics is not a prerequisite for cell migration/invasion, it is a transient event that concerns only few cells in a tumour mass. The induction of EMT depends on the tumour type and its genetic alterations as well as on its interaction with the extracellular matrix. In parallel, trials for EMT identification in clinical samples lack of a widely accepted methodology, nomenclature and reliable markers. This review summarizes the main EMT characteristics and proposes methodologies for better analysis in vitro. It also highlights recent studies identifying cells with EMT characteristics in human cancer and proposes certain markers to identify them in tumour samples. Finally, it cites the recent literature concerning the mechanisms of drug resistance related to EMT in the context of anti-tumour therapies and proposes related new targets for therapy.     

Diverse Regulation of YB-1 and YB-3 Abundance in Mammals

Biochemistry (Moscow) - YB proteins are DNA/RNA binding proteins, members of the family of proteins with cold shock domain. Role of YB proteins in the life of cells, tissues, and whole organisms is...     

Epithelial-mesenchymal transition and cancer stemness: the Twist1-Bmi1 connection

EMT (epithelial-mesenchymal transition), a major mechanism of cancer metastasis, is a process that generates cells with stem-like properties. These stem-like cells in tumours are described as cancer stem cells. The link between EMT and cancer stemness is well documented without detailed mechanistic proof. Bmi1 belongs to the PRC1 (polycomb repressive complex 1) maintaining self-renewal and stemness together with EZH2 (enhancer of zeste homologue 2), which is a component of PRC2. Bmi1 is frequently overexpressed in different types of human cancers. Recent demonstration of an EMT regulator, Twist1, directly regulating the expression of Bmi1 provides a mechanistic explanation of the relationship between EMT and cancer stemness. The functional interdependence between Twist1 and Bmi1 provides a fresh insight into the common mechanism mediating EMT and cancer stemness. This observation is also confirmed using head and neck cancer patient samples. These results provide a critical mechanism of Twist1-induced EMT and cancer stemness in cancer cells through chromatin remodelling. The role of hypoxia and microRNAs in regulating EMT and cancer stemness is also discussed.     

YB-1与肿瘤发生及治疗

Y-box结合蛋白(Y-box binding protein,YB)是一类广泛存在于从低等到高等多种生物中的蛋白质家族,在体内行使多种生物学功能.大量研究表明,YB-1作为该家族成员之一,与许多重要的生物大分子存在密切联系,并对细胞、组织和机体的生理机能产生重大影响.更为重要的是,YB-1在多种疾病,尤其是恶性肿瘤的发生和发展中也起到十分关键的作用,对癌细胞表型的维持及肿瘤多药耐药性(MDR)的产生具有全方位的影响.以YB-1为作用靶点的新型肿瘤治疗策略可望有效控制癌症患者病情恶化,改善耐药状况.现就对YB-1与肿瘤发生和发展之间关系的研究进展,以及针对YB-1治疗策略的制定作一评述和展望.     

An acidic protein, YBAP1, mediates the release of YB-1 from mRNA and relieves the translational repression activity of YB-1

Eukaryotic Y-box proteins are nucleic acid-binding proteins implicated in a wide range of gene regulatory mechanisms. They contain the cold shock domain, which is a nucleic acid-binding structure also found in bacterial cold shock proteins. The Y-box protein YB-1 is known to be a core component of messenger ribonucleoprotein particles (mRNPs) in the cytoplasm. Here we disrupted the YB-1 gene in chicken DT40 cells. Through the immunoprecipitation of an epitope-tagged YB-1 protein, which complemented the slow-growth phenotype of YB-1-depleted cells, we isolated YB-1-associated complexes that likely represented general mRNPs in somatic cells. RNase treatment prior to immunoprecipitation led to the identification of a Y-box protein-associated acidic protein (YBAP1). The specific association of YB-1 with YBAP1 resulted in the release of YB-1 from reconstituted YB-1-mRNA complexes, thereby reducing the translational repression caused by YB-1 in the in vitro system. Our data suggest that YBAP1 induces the remodeling of YB-1-mRNA complexes.     

Proteomics-based strategy to delineate the molecular mechanisms of RhoGDI2-induced metastasis and drug resistance in gastric cancer

Rho GDP dissociation inhibitor 2 (RhoGDI2) was initially identified as a regulator of the Rho family of GTPases. Our recent works suggest that RhoGDI2 promotes tumor growth and malignant progression, as well as enhances chemoresistance in gastric cancer. Here, we delineate the mechanism by which RhoGDI2 promotes gastric cancer cell invasion and chemoresistance using two-dimensional gel electrophoresis (2-DE) on proteins derived from a RhoGDI2-overexpressing SNU-484 human gastric cancer cell line and control cells. Differentially expressed proteins were identified using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF-MS). In total, 47 differential protein spots were identified; 33 were upregulated, and 14 were downregulated by RhoGDI2 overexpression. Upregulation of SAE1, Cathepsin D, Cofilin1, CIAPIN1, and PAK2 proteins was validated by Western blot analysis. Loss-of-function analysis using small interference RNA (siRNA) directed against candidate genes reveals the need for CIAPIN1 and PAK2 in RhoGDI2-induced cancer cell invasion and Cathepsin D and PAK2 in RhoGDI2-mediated chemoresistance in gastric cancer cells. These data extend our understanding of the genes that act downstream of RhoGDI2 during the progression of gastric cancer and the acquisition of chemoresistance.     

Loss of E-cadherin promotes the growth,invasion and drug resistance of colorectal cancer cells and is associated with liver metastasis

The recent studies indicated that the epithelial cell adhesion molecule E-cadherin is a well-recognized molecule that is important in cell adhesion. To further investigate the molecular basis of this notion, we used small-interfering RNA to inhibit E-cadherin function and found that loss of E-cadherin promoted Colorectal cancer cell growth, invasion and drug resistance through induction of β-catenin nuclear translocation and epithelial-to-mesenchymal transition. Further analysis of E-cadherin expression with clinicopathologic parameters showed that E-cadherin expression decreased in Colorectal cancer patients who developed liver metastasis (P = 0.043). These findings indicate that E-cadherin loss in tumors contributes to progression and metastatic dissemination. Thus, E-cadherin can act as a central modulator of the cell biological phenotypes and a potential prognostic marker in Colorectal cancer.     

Sirtuins at the crossroads of stemness,aging, and cancer

Sirtuins are stress‐responsive proteins that direct various post‐translational modifications (PTMs) and as a result, are considered to be master regulators of several cellular processes. They are known to both extend lifespan and regulate spontaneous tumor development. As both aging and cancer are associated with altered stem cell function, the possibility that the involvement of sirtuins in these events is mediated by their roles in stem cells is worthy of investigation. Research to date suggests that the individual sirtuin family members can differentially regulate embryonic, hematopoietic as well as other adult stem cells in a tissue‐ and cell type‐specific context. Sirtuin‐driven regulation of both cell differentiation and signaling pathways previously involved in stem cell maintenance has been described where downstream effectors involved determine the biological outcome. Similarly, diverse roles have been reported in cancer stem cells (CSCs), depending on the tissue of origin. This review highlights the current knowledge which places sirtuins at the intersection of stem cells, aging, and cancer. By outlining the plethora of stem cell‐related roles for individual sirtuins in various contexts, our purpose was to provide an indication of their significance in relation to cancer and aging, as well as to generate a clearer picture of their therapeutic potential. Finally, we propose future directions which will contribute to the better understanding of sirtuins, thereby further unraveling the full repertoire of sirtuin functions in both normal stem cells and CSCs.     

Innovative nano-carriers in anticancer drug delivery-a comprehensive review

In the scientific field, nanotechnology has offered multipurpose and designated functional nanoparticles (NPs) for the development of applications in nano-medicine. This present review focuses on cutting edge of nanotechnology in biomedical applications as drug carries in cancer treatment. The nanotechnology overcomes several limitations of drug delivery systems used in distinct therapeutic approaches of cancer treatment. The serious effect of conventional chemotherapeutics by nonspecific targeting, the lack of solubility, and the inability of chemotherapeutics entry to cancer cells which, offers a great opportunity for nanotechnology to play significant roles in cancer biology. The selective delivery of nano-drugs to the targeted cancer cells by the programmed way and avoiding nonspecific interactions to the healthy cells. The present review focuses on the methods of improving the size, shape and characteristics of nanomaterials which can be exploited for cancer therapy. The successful designing of nanocarriers can be tailored for cancer treatment for upcoming future as nano-medicines.