Long noncoding RNA TMEM147-AS1 serves as a microRNA-326 sponge to aggravate the malignancy of gastric cancer by upregulating SMAD5

The abnormal expression of long noncoding RNAs(lncRNAs)is frequently observed in gastric cancer(GC)and considered an important driving force in GC progression.However,little is known regarding the involvement of TMEM147-AS1 in GC.Therefore,we examined TMEM147-AS1 expression in GC and determined its prognostic value.In addition,TMEM147-AS1 expression was depleted to identify the functional changes in response to TMEM147-AS1 deficiency.Using the cancer genome atlas dataset and our own cohort,we identified a strong expression of TMEM147-AS1 in GC.Increased TMEM147-AS1 levels in GC showed a significant association with poor prognosis.TMEM147-AS1 interference resulted in the inhibition of GC cell proliferation,colony-forming,migration,and invasion in vitro.Additionally,depletion of TMEM147-AS1 restricted the growth of GC cells in vivo.Mechanistically,TMEM147-AS1 functioned as a microRNA-326(miR-326)sponge.Furthermore,SMAD family member 5(SMAD5)was experimentally validated as the functional effector of miR-326.TMEM147-AS1 was demonstrated to sequester miR-326 away from SMAD5;consequently,knocking down TMEM147-AS1 downregulated SMAD5 levels in GC cells.The functional suppression of miR-326 or reintroduction of SMAD5 effectively reversed the attenuated behavior of GC cells caused by TMEM147-AS1 downregulation.In summary,TMEM147-AS1 exhibits tumorigenic activities in GC,which is likely the result of an altered miR-326/SMAD5 axis.Therefore,targeting TMEM147-AS1/miR-326/SMAD5 may represent a target for the treatment of GC.

Not just a sponge:novel functions of circRNAs in cholangiocarcinoma

Cholangiocarcinoma(CCA)is one of the most common and highly malignant tumors,and its incidence and mortality rates are increasing yearly.Circular RNAs(circRNAs),a class of closed-loop non-coding RNAs formed by reverse splicing of exons or introns,play an essential regulatory role in CCA and have been a hot topic of medical research in recent years.In addition,about 80%of current research reports focus on the ability of circRNAs to sponge miRNAs in CCA.However,as research continues,circRNAs are more than just a sponge in CCA;they can also alter protein subcellular localization,encode proteins and affect other cells via extracellular vesicles(EVs).Interestingly,circRNAs not only serve as novel players in CCA pathogenesis but also as potential biomarkers and therapeutic targets for CCA.

CircDOCK7 facilitates the proliferation and adipogenic differentiation of chicken abdominal preadipocytes through the gga‑miR‑301b‑3p/ACSL1 axis

Background Abdominal fat deposition depends on both the proliferation of preadipocytes and their maturation into adipocytes,which is a well-orchestrated multistep process involving many regulatory molecules.Circular RNAs(circRNAs)have emergingly been implicated in mammalian adipogenesis.However,circRNA-mediated regulation in chicken adipogenesis remains unclear.Our previous circRNA sequencing data identified a differentially expressed novel circRNA,8:27,886,180|27,889,657,during the adipogenic differentiation of chicken abdominal preadipocytes.This study aimed to investigate the regulatory role of circDOCK7 in the proliferation and adipogenic differentiation of chicken abdominal preadipocytes,and explore its molecular mechanisms of competing endogenous RNA underlying chicken adipogenesis.Results Our results showed that 8:27,886,180|27,889,657 is an exonic circRNA derived from the head-to-tail splicing of exons 19–22 of the dedicator of cytokinesis 7(DOCK7)gene,abbreviated as circDOCK7.CircDOCK7 is mainly distributed in the cytoplasm of chicken abdominal preadipocytes and is stable because of its RNase R resistance and longer half-life.CircDOCK7 is significantly upregulated in the abdominal fat tissues of fat chickens compared to lean chickens,and its expression gradually increases during the proliferation and adipogenic differentiation of chicken abdominal preadipocytes.Functionally,the gain-and loss-of-function experiments showed that circDOCK7 promoted proliferation,G0/G1-to S-phase progression,and glucose uptake capacity of chicken abdominal preadipocytes,in parallel with adipogenic differentiation characterized by remarkably increased intracellular lipid droplet accumulation and triglyceride and acetyl coenzyme A content in differentiated chicken abdominal preadipocytes.Mechanistically,a pull-down assay and a dual-luciferase reporter assay confirmed that circDOCK7 interacted with gga-miR-301b-3p,which was identified as an inhibitor of chicken abdominal adipogenesis.Moreover,the ACSL1 gene was demonstrated to be a direct target of gga-miR-301b-3p.Chicken ACSL1 protein is localized in the endoplasmic reticulum and mitochondria of chicken abdominal preadipocytes and acts as an adipogenesis accelerator.Rescue experiments showed that circDOCK7 could counteract the inhibitory effects of gga-miR-301b-3p on ACSL1 mRNA abundance as well as the proliferation and adipogenic differentiation of chicken abdominal preadipocytes.Conclusions CircDOCK7 serves as a miRNA sponge that directly sequesters gga-miR-301b-3p away from the ACSL1 gene,thus augmenting adipogenesis in chickens.These findings may elucidate a new regulatory mechanism underlying abdominal fat deposition in chickens.

Cisplatin-based miRNA delivery strategy inspired by the circCPNE1/miR-330-3p pathway for oral squamous cell carcinoma

Circular RNAs(circRNAs)are ideal biomarkers of oral squamous cell carcinoma(OSCC)because of their highly stable closed-loop structure,and they can act as microRNA(miRNA)sponges to regulate OSCC progression.By analyzing clinical samples,we identified circCPNE1,a dysregulated circRNA in OSCC,and its expression level was negatively correlated with the clinical stage of OSCC patients.Gain-of-function assays revealed the tumor-suppressive effect of circCPNE1,which was then identified as a miR-330-3p sponge.MiR-330-3p was recognized as a tumor promoter in multiple studies,consistent with our finding that it could promote the proliferation,migration,and invasion of OSCC cells.These results indicated that selective inhibition of miR-330-3p could be an effective strategy to inhibit OSCC progression.Therefore,we designed cationic polylysine-cisplatin prodrugs to deliver antagomiR-330-3p(a miRNA inhibitory analog)via electrostatic interactions to form PP@miR nanoparticles(NPs).Paratumoral administration results revealed that PP@miR NPs effectively inhibited subcutaneous tumor progression and achieved partial tumor elimination(2/5),which confirmed the critical role of miR-330-3p in OSCC development.These findings provide a new perspective for the development of OSCC treatments.

Circular RNAs in pulmonary hypertension:Emerging biological concepts and potential mechanism

Circular RNAs(circRNAs)are endogenous RNAs with a covalently closed single-stranded transcript.They are a novel class of genomic regulators that are linked to many important development and disease processes and are being pursued as clinical and therapeutic targets.Using the most powerful RNA sequencing and bioinformatics techniques,a large number of circRNAs have been identified and further functional studies have been performed.It is known that circRNAs act as potential biomarkers,sponges for microRNAs(miRNAs)and RNA-binding proteins(RBPs),and regulators of mRNA transcription.They also participate in the translation of peptides or proteins.Many types of circRNAs are dysregulated in plasma or lung tissues,and they may be involved in regulating the proliferation and apoptosis of pulmonary artery endothelial cells(PAECs)and pulmonary artery smooth muscle cells(PASMCs),leading to pulmonary vascular remodeling in pulmonary hypertension(PH).One possible mechanism is that circRNAs can regulate the function of PAECs and PASMCs by acting as miRNA sponge.However,other potential mechanisms of action of circRNAs are still being actively explored in PH.This paper presents a systematic review of the biogenesis,biological characterization,relevant underlying functions,and future perspectives for studies of circRNAs in the pathogenesis of PH.

Long noncoding RNA PPP1R14B-AS1 imitates microRNA-134-3p to facilitate breast cancer progression by upregulating LIM and SH3 protein 1

Long noncoding RNA PPP1R14B antisense RNA 1(PPP1R14B-AS1)has emerged as a critical modulator of liver cancer and lung adenocarcinoma progression.However,the functional importance and biological relevance of PPP1R14B-AS1 in breast cancer remain unclear.Therefore,this study was designed to detect PPP1R14B-AS1 levels in breast cancer cells using qRT–PCR and elucidate the influence of PPP1R14B-AS1 on aggressive phenotypes.Furthermore,molecular events mediating the action of PPP1R14B-AS1 were characterized in detail.Functional experiments addressed the impacts of PPP1R14B-AS1 knockdown on breast cancer cells.In this study,PPP1R14B-AS1 was found to be overexpressed in breast cancer,exhibiting a close correlation with poor patient prognosis.Results also showed that breast cancer cell proliferation and motility were suppressed when PPP1R14B-AS1 was silenced.Mechanistically,PPP1R14B-AS1 acted as a competing endogenous RNA for microRNA-134-3p(miR-134-3p)in breast cancer cells.PPP1R14B-AS1 also increased LIM and SH3 protein 1(LASP1)levels by imitating miR-134-3p in breast cancer cells.Rescue experiments further corroborated that the knockdown of miR-134-3p or an increase in LASP1 restored the aggressive malignant characteristics of breast cancer cells that were weakened by PPP1R14B-AS1 depletion.In summary,PPP1R14B-AS1 facilitated the oncogenicity of breast cancer cells by controlling the miR-134-3p/LASP1 axis.We believe that ourfindings may contribute to the development of precision therapy techniques in thefield of breast cancer treatment.

Short Tandem Target Mimic:A Long Journey to the Engineered Molecular Landmine for Selective Destruction/Blockage of MicroRNAs in Plants and Animals

MicroRNAs（miRNAs） are a population of highly conserved specific small ribo-regulators that negatively regulate gene expressions in both plants and animals.They play a key role in post-transcriptional gene regulation by destabilizing the target gene transcripts or blocking protein translation from them.Interestingly,these negative regulators are largely compromised by an upstream layer of negative regulators ＂target mimics＂ found in plants or ＂endogenous competing RNAs＂ revealed recently in animals.These endogenous regulatory mechanisms of ＂double negatives making a positive＂ have now been developed into a key strategy in the study of small RNA functions. This review presents some reflections on the long journey to the short tandem target mimic（STTM） for selective destruction/blockage of specific miRNAs in plants and animals,and the potential applications of STTM are discussed.