MicroRNAs (miRNA) are a class of endogenous, small noncoding RNAs found in animals, plants, and viruses that control their target gene expression posttranscriptionally. They are involved in a wide array of biological processes including cell differentiation, development, cell death and homeostasis, and fine-tune the regulation of these pathways. Their aberrant expressions have been associated with different diseases. These small RNAs are also known to function as oncogenes, oncosupressor genes, modulators of metastatic spread, and regulators of cancer stem cells. Their deregulation is a hallmark of different cancers types including breast cancer. Despite the growing evidence for their involvement in breast cancer, understanding the interplay between miRNAs and their targets leading to the disease remains largely unknown. Here, we provide a comprehensive story on miRNA signatures of breast cancer, miRNAs in breast cancer stem cells, metastamirs (i.e., metastasis regulatory miRNAs), circulating miRNAs as invasive blood-based biomarkers, and oncomiRs and oncosupressor miRNAs associated with breast cancer. Furthermore, we provide biological insights on their regulation by various mechanisms including genomic alterations and demonstration of a complicated feedback network between miRNAs and epigenetic regulators forming an epigenetics-miRNA regulatory circuit whose disruption may underlie the cause of breast cancer. Mol Cancer Res; 11(4); 315-28. Ó2013 AACR.

Hepatocellular carcinoma (HCC) typically develops in a chronic inflammatory setting causal to release of a plethora of growth factors and cytokines. However, the molecular effect of these cytokines on HCC progression is poorly understood. In this study, we exposed HCC cells to TGF-β2 (Transforming Growth Factor-β2), which resulted in a significant elevation of EMT (Epithelial to Mesenchymal Transition) like features. Molecular analysis of EMT markers showed an increase at both RNA and protein levels upon TGF-β2 administration along with up-regulation of TGF-β-induced Smad signaling. Induction of EMT was associated with a simultaneous increase in reactive oxygen species (ROS) and cytostasis of TGF-β2-treated cells. Importantly, quenching of ROS resulted in a significant promotion of TGF-β2-induced EMT. Furthermore, cells treated with TGF-β2 also showed an enhanced autophagic flux. Interestingly, inhibition of autophagy by chloroquine-di-phosphate (CQDP) or siRNA-mediated ablation of ATG5 drastically inhibited TGF-β2-induced EMT. Autophagy inhibition significantly increased ROS levels promoting apoptosis. It was further observed that pro-inflammatory cytokine like, TNF-α (Tumor Necrosis Factor-α) can antagonize TGF-β2-induced response by down-regulating autophagy, increasing ROS levels and thus inhibiting EMT in HCC cells. This inhibitory effect of TNF-α is serum-independent. Transcriptomic analysis through RNA sequencing was further performed which validated that TGF-β2-induced autophagic genes are inhibited by TNF-α treatment suppressing EMT. Our study suggests that autophagy plays a pro-metastatic role facilitating EMT by regulating ROS levels in HCC cells and TNF-α can suppress EMT by inhibiting autophagy. We provide unique mechanistic insights into the role of TGF-β2 in HCC cells, along with appropriate cues to effectively control the disease.

In recent years, the use of silver nanoparticles (AgNPs) in biomedical applications has shown an unprecedented boost along with simultaneous expansion of rapid, high-yielding, and sustainable AgNP synthesis methods that can deliver particles with well-defined characteristics. The present study demonstrates the potential of metal-tolerant soil fungal isolate Penicillium shearii AJP05 for the synthesis of protein-capped AgNPs. The particles were characterized using standard techniques, namely, UV–visible spectroscopy, transmission electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. The anticancer activity of the biosynthesized AgNPs was analyzed in two different cell types with varied origin, for example, epithelial (hepatoma) and mesenchymal (osteosarcoma). The biological NPs (bAgNPs) with fungal-derived outer protein coat were found to be more cytotoxic than bare bAgNPs or chemically synthesized AgNPs (cAgNPs). Elucidation of the molecular mechanism revealed that bAgNPs induce cytotoxicity through elevation of reactive oxygen species (ROS) levels and induction of apoptosis. Upregulation of autophagy and activation of JNK signaling were found to act as a prosurvival strategy upon bAgNP treatment, whereas ERK signaling served as a prodeath signal. Interestingly, inhibition of autophagy increased the production of ROS, resulting in enhanced cell death. Finally, bAgNPs were also found to sensitize cells with acquired resistance to cisplatin, providing valuable insights into the therapeutic potential of bAgNPs. To the best of our knowledge, this is the first study that provides a holistic idea about the molecular mechanisms behind the cytotoxic activity of protein-capped AgNPs synthesized using a metal-tolerant soil fungus.

Osteosarcoma (OS) is an aggressive bone malignancy commonly observed in children and adolescents. Sub-optimal therapy for years has irretrievably compromised the chances of OS patient survival; also, lack of extensive research on this rare disease has hindered therapeutic development. Cisplatin, a common anti-tumor drug, is currently an integral part of treatment regime for OS along with methotrexate and doxorubicin. However, toxicity issues associated with combination module impede OS therapy. Also, despite the proven benefits of cisplatin, acquisition of resistance remains a concern with cisplatin-based therapy. This prompted us to investigate the molecular effects of cisplatin exposure and changes associated with acquired resistance in OS cells. Cisplatin shock was found to activate MAPK signaling and autophagy in OS cells. An activation of JNK and autophagy acted as pro-survival strategy, while ERK1/2 triggered apoptotic signals upon cisplatin stress. A crosstalk between JNK and autophagy was observed. Maximal sensitivity to cisplatin was obtained with simultaneous inhibition of both autophagy and JNK pathway. Cisplatin resistant cells were further developed by repetitive drug exposure followed by clonal selection. The resistant cells showed an altered signaling circuitry upon cisplatin exposure. Our results provide valuable cues to possible molecular alterations that can be considered for development of improved therapeutic strategy against osteosarcoma.

Three strong solid state emissive cyclometalated platinum(ii) complexes showing AIE property were synthesized and the feasibility of one of the dyes for cell imaging was reported.

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Synthesized two new bis-cyclometalated iridium(iii) complexes exhibiting strong AIE, studied their luminescence by spectroscopy and quantum chemical calculations and applied as a non-toxic bio-imaging probe for mitochondrial staining.

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