Zuoren Yu is currently a Professor at Tongji University School of Medicine, Research Center for Translational, Shanghai East Hospital. After obtaining PhD degree in 2003 from Chinese Academy of Medical Sciences, he started Post-doctoral training at University of Pennsylvania School of Medicine and Thomas Jefferson University Kimmel Cancer Center. In 2009, he was assigned for a Faculty position in the track of Research Assistant Professor at Thomas Jefferson University. After joining Tongji University in Shanghai in 2012, he has been focusing on non-coding RNA regulation of breast cancer stem cells related with drug sensitivity, tumour regeneration and cancer metastasis. His main research work includes: Finding cell cycle regulator CCND1 is involved in the regulation of miRNA biogenesis and histone H3K9 tri-methylation, finding a regulatory loop between CCND1 and miR-17/20 in breast cancer, and demonstrating a microenvironment-mediated heterotypic signalling through which miR-17/20 regulate cross talking between cancer cells and inhibit breast cancer cell migration and metastasis.
Small non-coding RNA-based diagnostic and therapeutic applications for human cancer are expected soon. Knocking down the expression level or blocking the function of oncogenic miRNAs is believed to be a promising strategy for cancer treatment. miRNAs loss-of-function phenotypes are mainly induced by chemically modified antisense oligonucleotides. Here, we develop an alternative inhibitor for miRNAs, termed as small RNA zipper. It is designed to bind to the 5’-half sequences of one molecule and the 3’-half sequences of another molecule of the target miRNA through a complementary interaction. The small RNA zipper can connect the target miRNA molecules end to end forming a DNA–RNA duplex with high affinity, high specificity and high stability. To avoid self-complementarity and to enhance binding specificity, LNA nucleosides were applied to synthesize the small RNA zipper. Two miRNAs, miR-221 and miR-17, were tested in human breast cancer cell lines, demonstrating the 70%-90% knockdown of miRNA levels by 30–50 nM small RNA zippers at 24-48 h after transfection. The effect of the miRNA zipper was not limited to the target miRNA, but also to the expression of iso-miRNAs. Let-7 family members and point mutated sequence were applied to further validate the specificity of the miRNA zippers. The miR-221 zipper shows capability in rescuing the expression of target genes of miR-221 and reversing the oncogenic function of miR- 221 in breast cancer cells. In addition, we demonstrate that the miR-221 zipper attenuates doxorubicin resistance with higher efficiency than anti-miR-221 in human breast cancer cells. Taken together, small RNA zippers are a novel type of miRNA inhibitors, which can be used to induce miRNA loss-of-function phenotypes and validate miRNA target genes.
Anne Li is a Senior at Wootton High School with interest in Biological Chemistry. She takes an active role in the STEM field at her schools as the President of both Chemistry Club and Biology Club. Through her experience with the National Chemistry Olympiad and internship at the National Foundation for Cancer Research, she has been able to apply what she has learned in the classroom to help the mission to find a cure for cancer.
Methionine is one of the amino acids that are subjected to oxidation, and can subsequently lead to loss of molecular bioactivities or induce certain health conditions. Typically multiple methionine residues are present in protein molecules, and their oxidation characteristics can be dramatically different. The secondary structures, hydrophobicity, local chain flexibility, and solvent accessibility are all contributing factors to the oxidation propensity of these methionine residues. In this work, a predictive model has been developed to correlate the methionine residual oxidation propensities with their aforementioned properties. The model proteins used in this study, including monoclonal antibodies, growth hormone, interferons, etc., have all been investigated experimentally on their methionine oxidation propensity, and well resolved protein crystal structures documented in RCSB Protein Data Bank (PDB). The crystal structures of these proteins were optimized using QwikMD simulation program (UIUC) to produce well solvated structures. These properties of each methionine residue in the proteins, including hydrophobicity, local chain flexibility, and solvent accessibility, etc., were quantified and a mathematical model was developed to correlate them with the rank ordering of their oxidation propensities reported in literatures. The model, once further validated, provides a qualitative prediction tool to rank order methionine oxidation propensity in protein molecules that are complementary to experimental investigation approaches.