Xun Zhu

MicroRNA-374a activates Wnt/β-catenin signaling to promote breast cancer metastasis

Tumor metastasis involves a series of biological steps during which the tumor cells acquire the ability to invade surrounding tissues and survive outside the original tumor site. During the early stages, the cancer cells undergo an epithelial-mesenchymal transition (EMT). Wnt/β-catenin signaling is known to drive EMT and metastasis. Here we report that Wnt/β-catenin signaling is hyperactivated in metastatic breast cancer cells that express microRNA 374a (miR-374a). In breast cancer cell lines, ectopic overexpression of miR-374a promoted EMT and metastasis both in vitro and in vivo. Furthermore, miR-374a directly targeted and suppressed multiple negative regulators of the Wnt/β-catenin signaling cascade, including WIF1, PTEN, and WNT5A. Notably, miR-374a was markedly upregulated in primary tumor samples from patients with distant metastases and was associated with poor metastasis-free survival. These results demonstrate that miR-374a maintains constitutively activated Wnt/β-catenin signaling and may represent a therapeutic target for early metastatic breast cancer.

Statistical Research on Marine Natural Products Based on Data Obtained between 1985 and 2008

Since the 1960s, more than 20,000 compounds were discovered from marine organisms. In this paper we performed a quantitative analysis for the novel marine natural products reported between 1985 and 2008. The data was extracted mainly from the reviews of Faulkner and Blunt [1–26]. The organisms producing these marine natural products are divided into three major biological classes: marine microorganisms (including phytoplankton), marine algae and marine invertebrate. The marine natural products are divided into seven classes based on their chemical structure: terpenoids, steroids (including steroidal saponins), alkaloids, ethers (including ketals), phenols (including quinones), strigolactones, and peptides. The distribution and the temporal trend of these classes (biological classes and chemical structure classes) were investigated. We hope this article provides a comprehensive perspective on the research of marine natural products.

miR-205 Targets PTEN and PHLPP2 to Augment AKT Signaling and Drive Malignant Phenotypes in Non–Small Cell Lung Cancer

AKT signaling is constitutively activated in various cancers, due in large part to loss-of-function in the PTEN and PHLPP phosphatases that act as tumor suppressor genes. However, AKT signaling is activated widely in non-small cell lung cancers (NSCLC) where genetic alterations in PTEN or PHLPP genes are rare, suggesting an undefined mechanism(s) for their suppression. In this study, we report upregulation of the oncomir microRNA (miR)-205 in multiple subtypes of NSCLC, which directly represses PTEN and PHLPP2 expression and activates both the AKT/FOXO3a and AKT/mTOR signaling pathways. miR-205 overexpression in NSCLC cells accelerated tumor cell proliferation and promoted blood vessel formation in vitro and in vivo. Conversely, RNA interference-mediated silencing of endogenous miR-205 abrogated these effects. The malignant properties induced by miR-205 in NSCLC cells were reversed by AKT inhibitors, FOXO3a overexpression, rapamycin treatment, or restoring PHLPP2 or PTEN expression. Mechanistic investigations revealed that miR-205 overexpression was a result of NF-κB-mediated transactivation of the miR-205 gene. Taken together, our results define a major epigenetic mechanism for suppression of PTEN and PHLPP2 in NSCLC, identifying a pivotal role for miR-205 in development and progression of this widespread disease.

Loss of miR-204 Expression Enhances Glioma Migration and Stem Cell-like Phenotype

Phenotypic similarities have long been recognized between subpopulations of glioma and neural stem cells. Many of these similar properties, including the robust abilities to self-renew, migrate, and invade, are hallmarks of glioma cells that render them extremely aggressive. However, the molecular mechanisms underlying this character, particularly in glioma stem-like cells that drive this disease, remain poorly understood. Here, we report the results of a differential miRNA expression screen that compared glioma and neural stem cells, where we found that miR-204 was markedly downregulated in both types of cells. Mechanistic investigations revealed that miR-204 simultaneously suppressed self-renewal, stem cell-associated phenotype, and migration of glioma cells by targeting the stemness-governing transcriptional factor SOX4 and the migration-promoting receptor EphB2. Restoring miR-204 expression in glioma cells suppressed tumorigenesis and invasiveness in vivo and increased overall host survival. Further evaluation revealed that the miR-204 promoter was hypermethylated and that attenuating promoter methylation was sufficient to upregulate miR-204 in glioma cells. Together, our findings reveal miR-204 as a pivotal regulator of the development of stem cell-like phenotypes and cell motility in malignant glioma cells.

Cytotoxic norsesquiterpene peroxides from the endophytic fungus Talaromyces flavus isolated from the mangrove plant Sonneratia apetala.

Four new norsesquiterpene peroxides, named talaperoxides A-D (1-4), as well as one known analogue, steperoxide B (5, or merulin A), have been isolated from a mangrove endophytic fungus, Talaromyces flavus. Their structures were elucidated mainly by 1D and 2D NMR. Structures of 1, 2, and 5 were further confirmed by single-crystal X-ray diffraction, and their absolute configurations were also determined using copper radiation. Cytotoxic activities of compounds 1-5 were evaluated in vitro against human cancer cell lines MCF-7, MDA-MB-435, HepG2, HeLa, and PC-3. Compounds 2 and 4 showed cytotoxicity against the five human cancer cell lines with IC50 values between 0.70 and 2.78 μg/mL.

miR-186 Downregulation Correlates with Poor Survival in Lung Adenocarcinoma, Where It Interferes with Cell-Cycle Regulation

Deeper mechanistic understanding of lung adenocarcinoma (non-small cell lung carcinoma, or NSCLC), a leading cause of cancer-related deaths overall, may lead to more effective therapeutic strategies. In analyzing NSCLC clinical specimens and cell lines, we discovered a uniform decrease in miR-186 (MIR186) expression in comparison with normal lung tissue or epithelial cell lines. miR-186 expression correlated with patient survival, with median overall survival time of 63.0 or 21.5 months in cases exhibiting high or low levels of miR-186, respectively. Enforced overexpression of miR-186 in NSCLC cells inhibited proliferation by inducing G(1)-S checkpoint arrest. Conversely, RNA interference-mediated silencing miR-186 expression promoted cell-cycle progression and accelerated the proliferation of NSCLC cells. Cyclin D1 (CCND1), cyclin-dependent kinase (CDK)2, and CDK6 were each directly targeted for inhibition by miR-186 and restoring their expression reversed miR-186-mediated inhibition of cell-cycle progression. The inverse relationship between expression of miR-186 and its targets was confirmed in NSCLC tumor xenografts and clinical specimens. Taken together, our findings established a tumor-suppressive role for miR-186 in the progression of NSCLC.

SZ-685C, a marine anthraquinone, is a potent inducer of apoptosis with anticancer activity by suppression of the Akt/FOXO pathway

Background and purpose:  The aims of this study were to investigate the anti‐cancer activity of SZ‐685C, an anthracycline analogue isolated from marine‐derived mangrove endophytic fungi, and to explore the molecular mechanisms underlying such activity.

Statistical research on the bioactivity of new marine natural products discovered during the 28 years from 1985 to 2012.

Every year, hundreds of new compounds are discovered from the metabolites of marine organisms. Finding new and useful compounds is one of the crucial drivers for this field of research. Here we describe the statistics of bioactive compounds discovered from marine organisms from 1985 to 2012. This work is based on our database, which contains information on more than 15,000 chemical substances including 4196 bioactive marine natural products. We performed a comprehensive statistical analysis to understand the characteristics of the novel bioactive compounds and detail temporal trends, chemical structures, species distribution, and research progress. We hope this meta-analysis will provide useful information for research into the bioactivity of marine natural products and drug development.

MiR-503 targets PI3K p85 and IKK-β and suppresses progression of non-small cell lung cancer

A microRNA usually has the ability to coordinately repress multiple target genes and therefore are associated with many pathological conditions such as human cancer. Our understanding of the biological roles of microRNAs in lung cancer, however, remains incomplete. In this study, we identified miR‐503 as a tumor‐suppressive microRNA in human non‐small cell lung carcinoma (NSCLC), whose expression level correlates inversely with overall survival in NSCLC patients. Ectopic expression of miR‐503 suppressed tumor cell proliferation and metastasis‐related traits in vitro as well as in vivo, supporting a anti‐cancer role of the microRNA in NSCLC progression. Mechanistic study revealed that oncogenic PI3K p85 and IKK‐β were direct targets of miR‐503. Overexpression of either PI3K p85 or IKK‐β partially restored the malignant properties of NSCLC cells in the presence of miR‐503. Taken together, our data demonstrate miR‐503 inhibits the malignant phenotype of NSCLC by targeting PI3K p85 and IKK‐β and might play a suppressive role in the pathogenesis of NSCLC, thus providing new insights in developing novel diagnostic and therapeutic approaches.

Three bianthraquinone derivatives from the mangrove endophytic fungus Alternaria sp. ZJ9-6B from the South China Sea.

Three new bianthraquinone derivatives, alterporriol K (1), L (2) and M (3), along with six known compounds were obtained from extracts of the endophytic fungus Alternaria sp. ZJ9-6B, isolated from the mangrove Aegiceras corniculatum collected in the South China Sea. Their structures were elucidated by one- and two-dimensional NMR spectroscopy, MS data analysis and circular dichroism measurements. Compounds 1, 2 and 3 were first isolated alterporriols with a C-2–C-2′ linkage. The crystallographic data of tetrahydroaltersolanol B (7) was reported for the first time. In the primary bioassays, alterporriol K and L exhibited moderate cytotoxic activity towards MDA-MB-435 and MCF-7 cells with IC50 values ranging from 13.1 to 29.1 μM.