HOMER3 promotes liver hepatocellular carcinoma cancer progression by -upregulating EZH2 and mediating miR-361/GPNMB axis.

Liver hepatocellular carcinoma (LIHC) is among the most lethal human cancers. Studies have shown that Homer scaffold protein 3 (HOMER3) plays important roles in various diseases and cancers, but its biological function and molecular mechanism in LIHC have never been investigated. Our study discovered the aberrantly high expression of HOMER3 and its promising diagnostic and prognostic significance in LIHC. Functionally, HOMER3 knockdown inhibited the proliferative and migrative abilities of LIHC cells and tumor growth in vivo. Mechanically, HOMER3 mediated the aggressiveness of LIHC cells via GPNMB. Meanwhile, miR-361 directly targeted GPNMB and attenuated LIHC progression by suppressing GPNMB expression. The regulatory effect of HOMER3 during LIHC progression was exerted through the miR-361/GPNMB axis. Furthermore, EZH2 supplementation or miR-361 depletion effectively abated the tumor-suppressive effect of HOMER3 knockdown on LIHC progression. In conclusion, HOMER3 mediated LIHC progression through the EZH2/miR-361/GPNMB axis.

Smart PROTACs Enable Controllable Protein Degradation for Precision Cancer Therapy.

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional chemicals that degrade proteins at the post-translational level, which represent an emerging therapeutic modality to fight cancer and other diseases. Although several PROTACs have now entered clinical trials, potential off-tissue side effects have resulted from nonspecific accumulation at non-cancerous sites after systemic administration, and this remains a major challenge. To this end, in the past 3 years, activatable PROTACs whose activity can only be launched on demand have gained tremendous momentum. In this review, we provide an overview of these new smart activatable PROTACs, which exert protein degradation action only in response to internal or external stimuli. We categorize these activatable PROTACs according to their activation mechanism contributed by different stimuli, including reduction-activatable, hypoxia-activatable, and enzyme-activatable PROTACs and photo-caged or photo-switchable PROTACs. The use of stimuli-responsive chemical blocks in these activatable PROTACs allows local activation of the antitumor effects while reducing the incidence of off-site side effects for precision cancer therapy. The design principle and category of smart PROTACs are introduced along with an overview of their therapeutic prospects and challenges.

Drugging the "undruggable" microRNAs.

As a naturally occurring class of gene regulators, microRNAs (miRNAs) have attracted much attention as promising targets for therapeutic development. However, RNAs including miRNAs have long been considered undruggable, and most efforts have been devoted to using synthetic oligonucleotides to regulate miRNAs. Encouragingly, recent findings have revealed that miRNAs can also be drugged with small molecules that directly target miRNAs. In this review paper, we give a summary of recently emerged small-molecule inhibitors (SMIs) and small-molecule degraders (SMDs) for miRNAs. SMIs are small molecules that directly bind to miRNAs to inhibit their biogenesis, and SMDs are bifunctional small molecules that upon binding to miRNAs induce miRNA degradation. Strategies for discovering SMIs and developing SMDs were summarized. Applications of SMIs and SMDs in miRNA inhibition and cancer therapy were also introduced. Overall, SMIs and SMDs introduced here have high potency and specificity in miRNA inhibition. We envision that these small molecules will pave the way for developing novel therapeutics toward miRNAs that were previously considered undruggable.

Small molecules with big roles in microRNA chemical biology and microRNA-targeted therapeutics.

MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression. Aberrant miRNA expression or function have close links with various human diseases. Therefore, therapeutic treatments with disease-associated miRNAs as targets are emerging. However, the intracellular miRNA networks are extremely complicated and poorly understood, which thus hinder the development of miRNA-targeted therapeutics. Small molecules that are able to regulate endogenous miRNAs hold great potential in both elucidation of miRNA networks and treatment of miRNA-related diseases. Herein, we summarize current strategies for discovery of small molecule modifiers of miRNAs, and we highlight aspects of miRNA cellular biology elucidated by using these small molecules and miRNA-targeted therapeutics realized by these small molecules. We envision that this area will expand dramatically in the near future and will ultimately contribute to a better understanding of miRNA-involved cellular processes and development of therapeutic agents for miRNA-associated diseases.

LncRNA­AB209371 promotes the epithelial­mesenchymal transition of hepatocellular carcinoma cells.

The zinc finger protein Snail1 is an important factor in the regulation of the epithelial­mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) cells. The present study demonstrated that the expression of Snail1 in HCC tissues was significantly higher compared with its expression in tissues adjacent to primary sites, as determined via western blotting. Furthermore, the results of a dual luciferase assay revealed that hsa­microRNA(miR)199a­5p negatively regulated the protein expression of Snail1 by binding to its 3' untranslated region. However, in a comparative analysis of primary HCC and its metastatic tissues using reverse transcription­quantitative polymerase chain reaction and western blotting, it was demonstrated that the expression of hsa­miR199a­5p and Snail1 in HCC metastatic tissues were significantly higher compared with primary lesions and an association between them identified that hsa­miR199a­5p lost its ability to negatively regulate Snail1. This result is contradictive to the fact that hsa­miR199a­5p inhibits the expression of the Snail1 protein. The present study hypothesized that the aberrant expression of long non­coding RNA was the cause of hsa­miR199a­5p inactivation based on loss of function rather than a reduction in content. The data collected in the present study confirmed the hypothesis that AB209371 binds to hsa­miR199a­5p and weakened the inhibitory effect of hsa­miR199a­5p on Snail1 expression. In addition, an in vitro EMT model was established in the present study by inducing HCC cells with TGF­ß1. The results revealed that AB209371 silencing effectively reversed the hsa­miR199a­5p mediated inhibition of EMT by negatively regulating Snail1 protein expression. Therefore, AB209371 silencing in combination with hsa­miR199a­5p expression may serve as an effective means to inhibit EMT in HCC cells. The present study also revealed that hsa­miR199a­5p/Snail1 exhibits a dominant regulatory effect in the EMT of HCC cells via a Snail1 recovery experiment. In conclusion, to the best of our knowledge, the present study confirmed for the first time that the high expression of AB209371 is favorable for the EMT in HCC cells and may be a direct cause of hsa­miR199a­5p inactivation (an HCC metastasis suppressor). Additionally, AB209371 silencing combined with hsa­miR199a­5p overexpression may be an effective means to inhibit the metastasis of HCC and the EMT of HCC cells.

MicroRNAs as novel endogenous targets for regulation and therapeutic treatments.

MicroRNAs (miRNAs) are small non-coding RNAs that have been identified as key endogenous biomolecules that are able to regulate gene expression at the post-transcriptional level. The abnormal expression or function of miRNAs has been demonstrated to be closely related to the occurrence or development of various human diseases, including cancers. Regulation of these abnormal miRNAs thus holds great promise for therapeutic treatments. In this review, we summarize exogenous molecules that are able to regulate endogenous miRNAs, including small molecule regulators of miRNAs and synthetic oligonucleotides. Strategies for screening small molecule regulators of miRNAs and recently reported small molecules are introduced and summarized. Synthetic oligonucleotides including antisense miRNA oligonucleotides and miRNA mimics, as well as delivery systems for these synthetic oligonucleotides to enter cells, that regulate endogenous miRNAs are also summarized. In addition, we discuss recent applications of these small molecules and synthetic oligonucleotides in therapeutic treatments. Overall, this review aims to provide a brief synopsis of recent achievements of using both small molecule regulators and synthetic oligonucleotides to regulate endogenous miRNAs and achieve therapeutic outcomes. We envision that these regulators of endogenous miRNAs will ultimately contribute to the development of new therapies in the future.

Mesoporous Silica Nanoparticles as Carriers for Intracellular Delivery of Nucleic Acids and Subsequent Therapeutic Applications.

Nucleic acids, including DNA, microRNA (miRNA), small interfering RNA (siRNA), and antisense oligonucleotide (ASO), are powerful gene regulators, which have been demonstrated as promising drug candidates for therapeutic treatments. Nevertheless, poor cellular membrane permeability and serum stability have greatly hindered the applications of nucleic acids in biomedicine. To address these issues, associate carriers that can encapsulate and protect nucleic acids are urgently required. Mesoporous silica nanoparticles (MSNs or MSNPs), which are nanomaterials with excellent biocompatibility, large surface area for functionalization, and tunable pore size for encapsulating different cargos, are emerging as novel and ideal biomaterials for different biomedical applications. In this review paper, we focus on the applications of MSNs in nucleic acid delivery and nucleic acid-guided therapeutic treatments. General strategies for the preparation of nucleic acid-MSN complexes will be firstly introduced, followed by a summary of recent applications of MSNs in nucleic acid delivery and nucleic acid-guided therapeutics.