MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

Soon after they were first described in 1990, aptamers were largely recognized as a new class of biological ligands that can rival antibodies in various analytical, diagnostic, and therapeutic applications. Aptamers are short single-stranded RNA or DNA oligonucleotides capable of folding into complex 3D structures, enabling them to bind to a large variety of targets ranging from small ions to an entire organism. Their high binding specificity and affinity make them comparable to antibodies, but they are superior regarding a longer shelf life, simple production and chemical modification, in addition to low toxicity and immunogenicity. In the past three decades, aptamers have been used in a plethora of therapeutics and drug delivery systems that involve innovative delivery mechanisms and carrying various types of drug cargos. However, the successful translation of aptamer research from bench to bedside has been challenged by several limitations that slow down the realization of promising aptamer applications as therapeutics at the clinical level. The main limitations include the susceptibility to degradation by nucleases, fast renal clearance, low thermal stability, and the limited functional group diversity. The solution to overcome such limitations lies in the chemistry of aptamers. The current review will focus on the recent arts of aptamer chemistry that have been evolved to refine the pharmacological properties of aptamers. Moreover, this review will analyze the advantages and disadvantages of such chemical modifications and how they impact the pharmacological properties of aptamers. Finally, this review will summarize the conjugation strategies of aptamers to nanocarriers for developing targeted drug delivery systems.

/pdf/aptamers-chemistry-chemical-modifications-and-conjugation-2gtm7lxuav.pdf

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies.

Notch signalling is involved in many aspects of cancer biology, including angiogenesis, tumour immunity and the maintenance of cancer stem-like cells. In addition, Notch can function as an oncogene and a tumour suppressor in different cancers and in different cell populations within the same tumour. Despite promising preclinical results and early-phase clinical trials, the goal of developing safe, effective, tumour-selective Notch-targeting agents for clinical use remains elusive. However, our continually improving understanding of Notch signalling in specific cancers, individual cancer cases and different cell populations, as well as crosstalk between pathways, is aiding the discovery and development of novel investigational Notch-targeted therapeutics.

Targeting Notch in oncology: the path forward.

// Yunlu Jia 1,2 , Yongxia Chen 1,2 , Qinchuan Wang 1,2 , Ushani Jayasinghe 3 , Xiao Luo 4 , Qun Wei 1,2 , Ji Wang 1,2 , Hanchu Xiong 1,2 , Cong Chen 1,2 , Bin Xu 1,2 , Wenxian Hu 1,2 , Linbo Wang 1,2 , Wenhe Zhao 1,2 and Jichun Zhou 1,2 1 Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China 2 Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China 3 Brown University, Providence, Rhode Island, USA 4 Department of Radiology, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China Correspondence to: Linbo Wang, email: // Wenhe Zhao, email: // Jichun Zhou, email: // Keywords : breast cancer, exosome, metastasis, drug resistance, cancer therapy Received : January 10, 2017 Accepted : March 10, 2017 Published : March 29, 2017 Abstract Exosomes are nano-sized membrane vesicles released by a variety of cell types, and are thought to play important roles in intercellular communications. In breast cancer, through horizontal transfer of various bioactive molecules, such as proteins and mRNAs, exosomes are emerging as local and systemic cell-to-cell mediators of oncogenic information and play an important role on cancer progression. This review outlines the current knowledge and concepts concerning the exosomes involvement in breast cancer pathogenesis (including tumor initiation, invasion and metastasis, angiogenesis, immune system modulation and tumor microenvironment) and cancer therapy resistance. Moreover, the potential use of exosomes as promising diagnostic and therapeutic biomarkers in breast cancer are also discussed.

/pdf/exosome-emerging-biomarker-in-breast-cancer-6m7ne2sz3y.pdf

Exosome: emerging biomarker in breast cancer

Natural killer cell membrane infused biomimetic liposomes for targeted tumor therapy

Doxorubicin is used to treat numerous types of tumors including breast cancer, yet dose-associated toxicities limit its clinical application. Here, we demonstrated a novel strategy by which to deliver doxorubicin to breast cancer cells by conjugating cancer cell-specific single-strand DNA aptamers with doxorubicin-encapsulated DOTAP:DOPE nanoparticles (NPs). We utilizing a whole-cell-SELEX strategy, and 4T1 cells with high invasive and metastatic potential were used as target cells, while non-invasive and non-metastatic 67NR cells were used as subtractive cells. Ten potential aptamers were generated after multi-pool selection. Studies on the selected aptamers revealed that SRZ1 had the highest and specific binding affinity to 4T1 cells. Then we developed SRZ1 aptamer-carried DOTAP:DOPE-DOX NPs. In vitro uptake results which were conducted by FACS indicated that the aptamer significantly promoted the uptake efficiency of DOTAP:DOPE-DOX NPs by 4T1 cells. ATPlite assay was performed to test 4T1, 67NR and NMuMG cell viability after treatment with free doxorubicin, DOTAP:DOPE-DOX particles and aptamer‑loaded DOTAP:DOPE-DOX particles. As expected, the aptamers effectively enhanced accumulation of doxorubicin in the 4T1 tumor tissues as determined by in vivo mouse body images and biodistribution analysis. Consistent with the in vitro findings, aptamer-conjugated doxorubicin-loaded DOTAP:DOPE particles markedly suppressed tumor growth and significantly increased the survival rate of 4T1 tumor-bearing mice. These studies demonstrated that aptamer SRZ1 could be a promising molecule for chemotherapeutic drug targeting deliver.

/pdf/targeted-delivery-of-doxorubicin-to-breast-cancer-cells-by-3nt9ilvc9j.pdf

Targeted delivery of doxorubicin to breast cancer cells by aptamer functionalized DOTAP/DOPE liposomes

Breast cancer is one of the most frequently occurring malignant tumors affecting women's health. At least one million new cases are diagnosed each year. Therefore, research that aims to identify strategies that inhibit the growth of breast cancer cells has become a primary worldwide focus. Traditional Chinese medicine (TCM) is regarded as a valuable resource in China, and numerous monomer compositions extracted from TCMs have been demonstrated to exhibit antitumor effects. The present study aimed to determine the impact of paeoniflorin (PF) on breast cancer cell proliferation and invasion, and to explore the mechanisms underlying its effects. Different concentrations of PF were applied to MCF‑7 cells at various time points and the Cell Counting kit‑8 assay was used to determine cell proliferation, a transwell invasion assay was employed to determine cell invasion, reverse transcription‑polymerase chain reaction was used to determine notch homolog‑1 (NOTCH‑1) and Hes family basic helix‑loop helix transcription factor (HES)‑1 mRNA expression levels, and western blotting was used to determine NOTCH‑1 and HES‑1 protein expression levels. The results demonstrated that PF inhibited the proliferation of MCF‑7 cells in a dose‑ and time‑dependent manner. Following treatment with different concentrations of PF, the total number of cells present in the PF‑treated groups was significantly lower when compared with the untreated control group (P<0.05). With increasing doses of PF, the rate of cell invasion significantly decreased, indicating a dose‑dependent association. NOTCH‑1 and HES‑1 mRNA expression levels were reduced when compared with the untreated control group, which reached a statistical significance following treatment with 15 and 30 µM PF (P<0.05). NOTCH‑1 and HES‑1 protein levels demonstrated a similar trend to the mRNA levels, whereby an increase in the concentration of PF was associated with a decrease in NOTCH‑1 and HES‑1 protein expression levels. The results of the present study therefore suggest that PF may inhibit the proliferation and invasiveness of breast cancer cells via inhibition of the NOTCH‑1 signaling pathway.

/pdf/paeoniflorin-influences-breast-cancer-cell-proliferation-and-587fz1cv7w.pdf

Paeoniflorin influences breast cancer cell proliferation and invasion via inhibition of the Notch‑1 signaling pathway

Acute influenza-associated myocarditis varies in clinical severity ranging between asymptomatic and fulminant varieties. The most severe cases can result in impaired cardiac function‑associated mortality; however, the mechanism underlying the development of viral myocarditis has yet to be fully elucidated. The present study investigated the apoptosis induced in H9C2 cardiomyocytes by infection with the H1N1pdm2009 virus. The H9C2 cells were transfected with nucleoprotein (NP)‑specific short hairpin (sh) RNA, and viral replication was re‑evaluated in H9C2 cells infected with the H1N1pdm2009 virus, as was the apoptosis induced by the virus. Reverse transcription‑quantitative polymerase chain reaction and western blot analysis were performed to measure the expression of NP and apoptosis‑associated molecules. A plaque forming assay was used to quantify viral replication in H9C2 cells. An MTT assay and flow cytometric analysis were performed to determine the virus‑associated alterations in cellular viability and apoptosis, respectively. Results demonstrated that the H1N1pdm2009 virus replicated effectively in H9C2 cells and promoted apoptosis in association with the viral infection. The expression levels of apoptosis‑associated markers, including released cytochrome c and activated caspase‑3 were markedly promoted in the H1N1pdm2009‑infected H9C2 cells. However, the NP‑specific shRNA‑mediated NP knockdown significantly inhibited viral infection in the cells. The virus‑induced apoptosis of the H9C2 cells was also significantly reduced by the shRNA, which occurred via a decrease in the number of apoptotic cells through downregulating the levels of apoptosis‑associated markers. Taken together, the present study demonstrated the key pathogenic role of NP in H1N1pdm2009‑induced apoptosis of cardiomyocytes, and this marker of the influenza virus may be important in influenza virus‑associated acute myocarditis. In addition, NP‑specific shRNA may be an effective agent for inhibiting influenza virus‑induced apoptosis in cardiomyocytes or in influenza virus‑associated acute myocarditis.

/pdf/shrna-mediated-np-knockdown-inhibits-the-apoptosis-of-2wu3mwy379.pdf

shRNA‑mediated NP knockdown inhibits the apoptosis of cardiomyocytes induced by H1N1pdm2009 influenza virus

Exosomes are a family of bioactive vesicles that are secreted from various types of cell, including tumor cells. Exosomes derived from breast cancer cells have been demonstrated to perform important functions in tumor progression in vitro and in vivo. However, few studies exist regarding the function of exosomes in CD133+ breast cancer cells. In the present study, exosomes from 4T1 mouse breast cancer cells and mouse mammary gland epithelial cells were purified. The exosome-associated markers CD63, CD9 and CD81 were detected, and the size distribution and ζ potential of the exosomes were determined. Exosome uptake by CD133+ and CD133-4T1 cells was confirmed by confocal microscopy. An ATPlite assay indicated that the proliferation of CD133+ cells was increased and the apoptosis was suppressed by exosomes from 4T1 cells. Collectively, the findings of the present study demonstrate a novel mechanism by which the action of exosomes on CD133+ 4T1 cells may contribute to breast cancer progression.

/pdf/exosomes-from-breast-cancer-cells-stimulate-proliferation-4x1vscnfc0.pdf

Exosomes from breast cancer cells stimulate proliferation and inhibit apoptosis of CD133+ cancer cells in vitro.

Despite advances in the understanding of breast cancer, patients most commonly have a poor prognosis, particularly those with triple negative breast cancer (TNBC). microRNAs (miRNAs) are endogenous non‑coding small RNAs, and their aberrant expression is linked to numerous malignancies. In the present study, the expression levels of miR‑200c in patients with TNBC were analyzed and it was identified that miR‑200c was downregulated in TNBC samples, compared with that in normal adjacent tissues. miR‑200c was overexpressed in the TNBC cell line MDA‑MB‑231 and its functions were studied in vitro and in vivo. An in vitro study revealed that the overexpression of miR‑200c inhibited MDA‑MB‑231 cell proliferation and resulted in the induction of apoptosis. The in vivo data indicated that the overexpression of miR‑200c significantly inhibited tumor growth and increased the rate of apoptosis. Target prediction revealed that the X‑linked inhibitor of apoptosis (XIAP) had putative complementary sequences to miR‑200c, which was confirmed by a dual luciferase reporter assay. Western blot analysis further demonstrated that the expression of XIAP was markedly reduced and that caspase‑3 was highly activated by the overexpression of miR‑200c. These findings suggested that miR‑200c may function as a tumor suppressor gene in TNBC, at least partly via directly targeting XIAP, and may therefore act as a potential therapeutic target in the development of novel treatment strategies for TNBC.

/pdf/microrna-200c-downregulates-xiap-expression-to-suppress-3e5onswdsp.pdf

microRNA-200c downregulates XIAP expression to suppress proliferation and promote apoptosis of triple-negative breast cancer cells.

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