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Background: Radiotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC); however, almost 20% of patients experience treatment failure due to radioresistance. Therefore, understanding the mechanisms of radioresistance is imperative. HOTAIRM1 is deregulated in various human cancers, yet its role in NPC radioresistance are largely unclear. Methods: This study investigated the association between HOTAIRM1 and radioresistance using CCK8, flow cytometry, and comet assays. Additionally, xenograft mice and patient-derived xenografts (PDX) models were employed to elucidate the biological functions of HOTAIRM1, and transcriptomic RNA sequencing was utilized to identify its target genes. Results: Our study revealed an upregulation of HOTAIRM1 levels in radioresistant NPC cell lines and tissues. Furthermore, a positive correlation was noted between high HOTAIRM1 expression and increased NPC cell proliferation, reduced apoptosis, G2/M cell cycle arrest, and diminished cellular DNA damage following radiotherapy. HOTAIRM1 modulates the acetylation and stability of the FTO protein, and inhibiting FTO elevates the m6A methylation level of CD44 precursor transcripts in NPC cells. Additionally, silencing the m6A reading protein YTHDC1 was found to increase the expression of CD44V. HOTAIRM1 enhances NPC cell resistance to ferroptosis and irradiation through the HOTAIRM1-FTO-YTHDC1-CD44 axis. Mechanistically, HOTAIRM1 interacts with the FTO protein and induces m6A demethylation of the CD44 transcript. The absence of m6A modification in the CD44 transcript prevents its recognition by YTHDC1, resulting in the transition from CD44S to CD44V. An abundance of CD44V suppresses ferroptosis induced by irradiation and contributes to NPC radioresistance. Conclusions: In conclusion, the results in this study support the idea that HOTAIRM1 stimulates CD44 alternative splicing via FTO-mediated demethylation, thereby attenuating ferroptosis induced by irradiation and promoting NPC radioresistance.

Emphysema, myofibroblast accumulation and airway remodeling can occur in the lungs due to exposure to atmospheric pollution, especially fine particulate matter (PM2.5), leading to chronic obstructive pulmonary disease (COPD). Specifically, bronchial epithelium-fibroblast communication participates in airway remodeling, which results in COPD. An increasing number of studies are now being conducted on the role of exosome-mediated cell-cell communication in disease pathogenesis. Here, we investigated whether exosomes generated from bronchial epithelial cells could deliver information to normal stromal fibroblasts and provoke cellular responses, resulting in airway obstruction in COPD. We studied the mechanism of exosome-mediated intercellular communication between human bronchial epithelial (HBE) cells and primary lung fibroblasts (pLFs). We found that PM2.5-induced HBE-derived exosomes promoted myofibroblast differentiation in pLFs. Then, the exosomal lncRNA expression profiles derived from PM2.5-treated HBE cells and nontreated HBE cells were investigated using an Agilent Human LncRNA Array. Combining coculture assays and direct exosome treatment, we found that HBE cell-derived exosomal HOTAIRM1 facilitated the myofibroblast differentiation of pLFs. Surprisingly, we discovered that exosomal HOTAIRM1 enhanced pLF proliferation to secrete excessive collagen secretion, leading to airway obstruction by stimulating the TGF-β/SMAD3 signaling pathway. Significantly, PM2.5 reduced FEV1/FVC and FEV1 and increased the level of serum exosomal HOTAIRM1 in healthy people; moreover, serum exosomal HOTAIRM1 was associated with PM2.5-related reductions in FEV1/FVC and FVC. These findings show that PM2.5 triggers alterations in exosome components and clarify that one of the paracrine mediators of myofibroblast differentiation is bronchial epithelial cell-derived HOTAIRM1, which has the potential to be an effective prevention and therapeutic target for PM2.5-induced COPD. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) are RNA molecules of 200 nucleotides or more in length that are not translated into proteins. Their expression is tissue-specific, with the vast majority involved in the regulation of cellular processes and functions. Many human diseases, including cancer, have been shown to be associated with deregulated lncRNAs, rendering them potential therapeutic targets and biomarkers for differential diagnosis. The expression of lncRNAs in the nervous system varies in different cell types, implicated in mechanisms of neurons and glia, with effects on the development and functioning of the brain. Reports have also shown a link between changes in lncRNA molecules and the etiopathogenesis of brain neoplasia, including glioblastoma multiforme (GBM). GBM is an aggressive variant of brain cancer with an unfavourable prognosis and a median survival of 14–16 months. It is considered a brain-specific disease with the highly invasive malignant cells spreading throughout the neural tissue, impeding the complete resection, and leading to post-surgery recurrences, which are the prime cause of mortality. The early diagnosis of GBM could improve the treatment and extend survival, with the lncRNA profiling of biological fluids promising the detection of neoplastic changes at their initial stages and more effective therapeutic interventions. This review presents a systematic overview of GBM-associated deregulation of lncRNAs with a focus on lncRNA fingerprints in patients' blood. [ABSTRACT FROM AUTHOR]

Despite the substantial progress in deciphering the pathogenesis of atherosclerosis (AS), cardiovascular mortality is still increasing. Therefore, atherosclerotic cardiovascular disease remains a sweeping epidemic that jeopardizes human health. Disentangling the molecular underpinnings of AS is imperative in the molecular cardiology field. Overwhelming evidence has indicated that the recognition of a fascinating class of players, known as long non-coding RNAs (lncRNAs), provides causality for coordinating AS. However, the function and mechanism of HOTAIRM1 are still poorly understood in human umbilical vein endothelial cells (HUVECs) and AS. Herein, we primarily underscored that lncRNA HOTAIRM1 is potentially responsible for AS; as such, it was dramatically up-regulated in HUVECs upon ox-LDL stimulation. Functionally, HOTAIRM1 knockdown attenuated HUVEC proliferation and potentiated apoptosis in the absence and presence of ox‐LDL. Furthermore, HOTAIRM1 was preferentially located in the nuclei of HUVECs. Mechanistically, HOXA4 is directly bound to the HOTAIRM1 promoter and activated its transcription. Of note, a positive feedback signaling between HOXA4 and HOTAIRM1 was determined. Intriguingly, the interplay between HOTAIRM1 and HSPA5 occurred in an RNA-binding protein pattern and a transcription-dependent regulatory manner. In addition, HSPA5 overexpression partially antagonized HUVEC proliferation inhibition of HOTAIRM1 depletion. Taken together, our findings delineate a pivotal functional interaction among HOXA4, HOTAIRM1, and HSPA5 as a novel regulatory circuit for modulating HUVEC proliferation. An in-depth investigation of the HOXA4-HOTAIRM1-HSPA5 axis promises to yield significant breakthroughs in identifying the molecular mechanisms governing AS and developing therapeutic avenues for AS. [ABSTRACT FROM AUTHOR]

Abstract Background HOTAIRM1 is revealed to facilitate the malignant progression of glioma. Vasculogenic mimicry (VM) is critically involved in glioma progression. Nevertheless, the molecular mechanism of HOTAIRM1 in regulating glioma VM formation remains elusive. Thus, we attempted to clarify the role and mechanism of HOTAIRM1 in VM formation in glioma. Methods qRT-PCR and western blot assays were used to evaluate the gene and protein expression levels of HOTAIRM1 in glioma patient tissue samples and cell lines. The role of HOTAIRM1 in glioma cell progression and VM formation was explored using a series of function gain-and-loss experiments. RNA-binding protein immunoprecipitation (RIP), RNA pull-down, and mechanism experiments were conducted to assess the interaction between HOTAIRM1/METTL3/IGFBP2 axis. Furthermore, rescue assays were conducted to explore the regulatory function of HOTAIRM1/METTL3/IGFBP2 in glioma cell cellular processes and VM formation. Results We found that HOTAIRM1 presented up-regulation in glioma tissues and cells and overexpression of HOTAIRM1 facilitated glioma cell proliferation, migration, invasion, and VM formation. Furthermore, overexpression of HOTAIRM1 promoted glioma tumor growth and VM formation capacity in tumor xenograft mouse model. Moreover, HOTAIRM1 was demonstrated to interact with IGFBP2 and positively regulated IGFBP2 expression. IGFBP2 was found to promote glioma cell malignancy and VM formation. Mechanistically, METTL3 was highly expressed in glioma tissues and cells and was bound with HOTAIRM1 which stabilized HOTAIRM1 expression. Rescue assays demonstrated that METTL3 silencing counteracted the impact of HOTAIRM1 on glioma cell malignancy and VM formation capacity. Conclusion HOTAIRM1, post-transcriptionally stabilized by METTL3, promotes VM formation in glioma via up-regulating IGFBP2 expression, which provides a new direction for glioma therapy. Graphical Abstract

Background: HOTAIRM1 is revealed to facilitate the malignant progression of glioma. Vasculogenic mimicry (VM) is critically involved in glioma progression. Nevertheless, the molecular mechanism of HOTAIRM1 in regulating glioma VM formation remains elusive. Thus, we attempted to clarify the role and mechanism of HOTAIRM1 in VM formation in glioma. Methods: qRT-PCR and western blot assays were used to evaluate the gene and protein expression levels of HOTAIRM1 in glioma patient tissue samples and cell lines. The role of HOTAIRM1 in glioma cell progression and VM formation was explored using a series of function gain-and-loss experiments. RNA-binding protein immunoprecipitation (RIP), RNA pull-down, and mechanism experiments were conducted to assess the interaction between HOTAIRM1/METTL3/IGFBP2 axis. Furthermore, rescue assays were conducted to explore the regulatory function of HOTAIRM1/METTL3/IGFBP2 in glioma cell cellular processes and VM formation. Results: We found that HOTAIRM1 presented up-regulation in glioma tissues and cells and overexpression of HOTAIRM1 facilitated glioma cell proliferation, migration, invasion, and VM formation. Furthermore, overexpression of HOTAIRM1 promoted glioma tumor growth and VM formation capacity in tumor xenograft mouse model. Moreover, HOTAIRM1 was demonstrated to interact with IGFBP2 and positively regulated IGFBP2 expression. IGFBP2 was found to promote glioma cell malignancy and VM formation. Mechanistically, METTL3 was highly expressed in glioma tissues and cells and was bound with HOTAIRM1 which stabilized HOTAIRM1 expression. Rescue assays demonstrated that METTL3 silencing counteracted the impact of HOTAIRM1 on glioma cell malignancy and VM formation capacity. Conclusion: HOTAIRM1, post-transcriptionally stabilized by METTL3, promotes VM formation in glioma via up-regulating IGFBP2 expression, which provides a new direction for glioma therapy. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS), which is a common and aggressive primary bone malignancy, occurs mainly in children and adolescent. Long noncoding RNAs (lncRNAs) are reported to play a pivotal role in various cancers. Here, we found that the lncRNA HOTAIRM1 is upregulated in OS cells and tissues. A set of functional experiments suggested that HOTAIRM1 knockdown attenuated the proliferation and stimulated the apoptosis of OS cells. A subsequent mechanistic study revealed that HOTAIRM1 functions as a competing endogenous RNA to elevate ras homologue enriched in brain (Rheb) expression by sponging miR‐664b‐3p. Immediately afterward, upregulated Rheb facilitates proliferation and suppresses apoptosis by promoting the mTOR pathway‐mediated Warburg effect in OS. In summary, our findings demonstrated that HOTAIRM1 promotes the proliferation and suppresses the apoptosis of OS cells by enhancing the Warburg effect via the miR‐664b‐3p/Rheb/mTOR axis. Understanding the underlying mechanisms and targeting the HOTAIRM1/miR‐664b‐3p/Rheb/mTOR axis are essential for OS clinical treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common malignant cancers in humans and has a high fatality rate. Despite pharmacological advances such as sorafenib and lenvatinib approval, responses are seen only in a limited fraction of HCCs, and the majority of HCC patients do not benefit from this treatment. In recent years, researchers have verified that the long noncoding RNAs (lncRNAs) impact the efficiency of lenvatinib and the prognosis of patients with HCC. Materials and methods This work obtained gene expression profile from an Arraystar lncRNA microarray. Expression of HOTAIRM1, Beclin-1, and p62 in HCC was characterized in clinical HCC tissues of 24 patients with HCC. Overexpression and knockdown experiments were performed in HCC cells to examine the effects of the HOTAIRM1 on lenvatinib sensitivity. The interactions between HOTAIRM1, miR-34a and Beclin-1 were predicted according to GSEA and CNC network. The effects of HOTAIRM1, autophagy and lenvatinib on tumor inhibit were validated in orthotopic tumor-bearing nude mouse model. Results Lenvatinib-resistant HCC cell lines were established using the concentration gradient method. Data from an Arraystar lncRNA microarray indicated that HOTAIRM1, a specific lncRNA located in an evolutionarily highly conserved HOX gene cluster, was differentially expressed between lenvatinib-resistant HCC cells and their parental cells. Expression of HOTAIRM1 and Beclin-1 in HCC was characterized in clinical HCC tissues of 24 patients who have different sensitivity to lenvatinib. Knocking down of HOTAIRM1 decreased the autophagy level in lenvatinib-resistant HCC cells and increased their sensitivity to lenvatinib, especially when combined with autophagy inhibitors both in vitro and in vivo. Further study indicated that knocking down HOTAIRM1 in lenvatinib-resistant cell lines increased the level of miR-34a and inhibited the expression of Beclin-1 in Huh7-R and HepG2-R cells. Investigation according to GSEA and CNC network, lncRNA and nearby coding gene and lncRNA-miRNA analyses demonstrated that the resistance of HCC to lenvatinib was affected by the HOTAIRM1-miR-34a-Beclin-1 regulatory axis. Conclusion HOTAIRM1 is an independent drug resistance factor which significantly associated with the efficacy of lenvatinib in HCC. HOTAIRM1 may downregulation of miR-34a and upregulation of Beclin-1, leading to activation of autophagy, thereby inducing lenvatinib resistance in HCC.

Chen T, Gao F, Yang T, et al. Cancer Manag Res. 2020;12:4379–7390. We, the Editors and Publisher of Cancer Management and Research, have retracted the following article. Following publication of the article, concerns were raised about the duplication of images from Figures 2, 5, 6, and 7 with images from other unrelated articles. Specifically, Images for Figures 2C and 7B have been duplicated with images for Figure 2C and Figure 6A from Zhang RN, Wu DM, Wu LP, Gao GW. LncRNA LINC00337 sponges mir-1285-3p to promote proliferation and metastasis of lung adenocarcinoma cells by upregulating YTHDF1. Cancer Cell Int. 2021;21:550. https://doi.org/10.1186/s12935-021-02253-8; Figure 3D from Zhang K, Shao CX, Zhu JD, et al. Exosomes function as nanoparticles to transfer miR-199a-3p to reverse chemoresistance to cisplatin in hepatocellular carcinoma. Biosci Rep. 2020;40(7):BSR20194026. doi: https://doi.org/10.1042/BSR20194026 (RETRACTED) and Figure 7A from Jiang X, Chen D. Circular RNA hsa_circ_0000658 inhibits osteosarcoma cell proliferation and migration via the miR-1227/IRF2 axis. J Cell Mol Med. 2021;25:510–520. https://doi.org/10.1111/jcmm.16105. Images for Figure 5B have been duplicated with images for Figure 5E from Du C, Zhang J, Wang Y, et al. The Long Non-coding RNA LINC01705 Regulates the Development of Breast Cancer by Sponging miR-186-5p to Mediate TPR Expression as a Competitive Endogenous RNA. Front Genet. 2020;11:779. https://doi.org/10.3389/fgene.2020.00779. Images for Figure 6E have been duplicated with images for Figure 5f from Shi X, Liu Z, Liu Z, et al. Long noncoding RNA PCAT6 functions as an oncogene by binding to EZH2 and suppressing LATS2 in non-small-cell lung cancer. EBioMedicine. 2018;37:177-187. https://doi.org/10.1016/j.ebiom.2018.10.004. In addition, the image for Figure 3B, H1650, sh-NC has been duplicated with the image for Figure 7C, H1650(sh-HOTAIRM1), anti-miR-498. The authors did not respond to our queries and were unable to provide an explanation for the duplicated images or provide data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors were notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Background: Bone marrow mesenchymal stem cells (BMSCs) can differentiate into osteoblasts and thus present a tremendous therapeutic potential in osteoporosis. Here, we elucidated the involvement of long non-coding RNAs (lncRNAs) HOXA transcript antisense RNA, myeloid-specific 1 (HOTAIRM1) in the osteogenic differentiation of BMSCs. Methods and results: The expression levels of HOTAIRM1, miR-152-3p, ETS proto-oncogene 1 (ETS1), runt-related transcription factor 2 (RUNX2), Osterix, and osteocalcin (OCN) were determined by a quantitative real-time polymerase chain reaction (qRT-PCR) or western blot method. Targeted relationship between miR-152-3p and HOTAIRM1 or ETS1 was confirmed by dual-luciferase reporter and RNA pull-down assays. The activity of alkaline phosphatase (ALP) was measured by the ALP Activity Assay Kit. The extent of the calcium deposition was assessed by Alizarin Red Staining. Our data showed that HOTAIRM1 and ETS1 levels were up-regulated and miR-152-3p expression was down-regulated during osteogenic differentiation of human BMSCs (HBMSCs). HOTAIRM1 overexpression enhanced osteogenic differentiation of HBMSCs, and decreased level of HOTAIRM1 suppressed osteogenic differentiation of HBMSCs. HOTAIRM1 directly targeted miR-152-3p. ETS1 was identified as a direct and functional target of miR-152-3p. Furthermore, HOTAIRM1 functioned as a post-transcriptional regulator of ETS1 expression by miR-152-3p. Conclusion: The findings in this paper identify HOTAIRM1 as a novel regulator of osteogenic differentiation of BMSCs by the regulation of miR-152-3p/ETS1 axis, uncovering HOTAIRM1 as a promising therapeutic strategy for osteoporosis. [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous entity encompassing distinct endotypes and varying phenotypes, characterized by common clinical manifestations, such as shortness of breath, wheezing, and variable airflow obstruction. Two major asthma endotypes based on molecular patterns are described: type 2 endotype (allergic-asthma) and T2 low endotype (obesity-related asthma). Long noncoding RNAs (lncRNAs) are transcripts of more than 200 nucleotides in length, currently involved in many diverse biological functions, such as chromatin remodeling, gene transcription, protein transport, and microRNA processing. Despite the efforts to accurately classify and discriminate all the asthma endotypes and phenotypes, if long noncoding RNAs could play a role as biomarkers in allergic asthmatic and adolescent obesity-related asthma, adolescents remain unknown. To compare expression levels of lncRNAs: HOTAIRM1, OIP5-AS1, MZF1-AS1, and GAS5 from whole blood of Healthy Adolescents (HA), Obese adolescents (O), allergic asthmatic adolescents (AA) and Obesity-related asthma adolescents (OA). We measured and compared expression levels from the whole blood of the groups mentioned above through RT-q-PCR. We found differentially expressed levels of these lncRNAs between the groups of interest. In addition, we found a discriminative value of previously mentioned lncRNAs between studied groups. Finally, we generated an interaction network through bioinformatics. Expression levels of OIP5-AS1, MZF1-AS1, HOTAIRM1, and GAS5 in whole blood from the healthy adolescent population, obese adolescents, allergic asthma adolescents, and obesity-related asthma adolescents are differently expressed. Moreover, these lncRNAs could act as molecular biomarkers that help to discriminate between all studied groups, probably through molecular mechanisms with several genes and miRNAs implicated. [ABSTRACT FROM AUTHOR]

Vasculogenic mimicry (VM) has been reported to accelerate angiogenesis in malignant tumors, yet the mechanism underlying VM has not been fully elucidated. N6‐methyladenosine (m6A) mainly modulates mRNA fate and affects multiple tumorigenesis. Here, we aimed to investigate m6A‐modified HOXA transcript antisense RNA myeloid‐specific 1 (HOTAIRM1) in the regulation of glioma‐associated VM formation. Gene expression was analyzed by quantitative RT‐PCR. Cell viability, metastases, and VM formation capacity were determined by CCK‐8, migration and invasion, as well as tube formation assays, respectively. The function and mechanisms of m6A‐modified HOTAIRM1 were defined through liquid chromatography–tandem mass spectrometry m6A quantification, methylated RNA immunoprecipitation sequencing, RNA stability assays, and RNA pull‐down experiments. A glioma xenograft mouse model was further established for VM evaluation in vivo. The results showed that HOTAIRM1, methyltransferase‐like 3 (METTL3), and insulin‐like growth factor binding protein 2 (IGFBP2) were upregulated in glioma tissues and cell lines. HOTAIRM1 functions as an oncogene in glioma progression; however, knockdown of HOTAIRM1 significantly reduced cell viability, migration, invasion, and VM formation. Notably, METTL3‐dependent m6A modification enhanced HOTAIRM1 mRNA stability, whereas knockdown of METTL3 deficiency significantly suppressed VM in glioma. Moreover, HOTAIRM1 was found to bind IGFBP2, and HOTAIRM1 deficiency blocked glioma progression and VM formation in vivo. Our results indicated that METTL3‐dependent m6A‐modified HOTAIRM1 promoted VM formation in glioma. [ABSTRACT FROM AUTHOR]

Propofol, an intravenous sedative-hypnotic agent, is demonstrated to have antioxidant properties. The purpose of this study is to investigate the functional roles of propofol in neuroblastoma cells.

Radiotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC); however, almost 20% of patients experience treatment failure due to radioresistance. Therefore, understanding the mechanisms of radioresistance is imperative. HOTAIRM1 is deregulated in various human cancers, yet its role in NPC radioresistance are largely unclear. This study investigated the association between HOTAIRM1 and radioresistance using CCK8, flow cytometry, and comet assays. Additionally, xenograft mice and patient-derived xenografts (PDX) models were employed to elucidate the biological functions of HOTAIRM1, and transcriptomic RNA sequencing was utilized to identify its target genes. Our study revealed an upregulation of HOTAIRM1 levels in radioresistant NPC cell lines and tissues. Furthermore, a positive correlation was noted between high HOTAIRM1 expression and increased NPC cell proliferation, reduced apoptosis, G2/M cell cycle arrest, and diminished cellular DNA damage following radiotherapy. HOTAIRM1 modulates the acetylation and stability of the FTO protein, and inhibiting FTO elevates the m6A methylation level of CD44 precursor transcripts in NPC cells. Additionally, silencing the m6A reading protein YTHDC1 was found to increase the expression of CD44V. HOTAIRM1 enhances NPC cell resistance to ferroptosis and irradiation through the HOTAIRM1-FTO-YTHDC1-CD44 axis. Mechanistically, HOTAIRM1 interacts with the FTO protein and induces m6A demethylation of the CD44 transcript. The absence of m6A modification in the CD44 transcript prevents its recognition by YTHDC1, resulting in the transition from CD44S to CD44V. An abundance of CD44V suppresses ferroptosis induced by irradiation and contributes to NPC radioresistance. In conclusion, the results in this study support the idea that HOTAIRM1 stimulates CD44 alternative splicing via FTO-mediated demethylation, thereby attenuating ferroptosis induced by irradiation and promoting NPC radioresistance. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a prevalent type of neurodegenerative disorder. AVE0991, a non-peptide analogue of Ang-(1-7), by which the progression of PD has been discovered to be ameliorated, but the specific mechanism whereby AVE0991 modulates the progression of PD re-mains unclear. The mice overexpressing human α-syn (A53T) were established to simulate PD pathology, and we also constructed an in vitro model of mouse dopaminergic neurons overexpressing hα-syn (A53T). The [ 18 F] FDG-PET/CT method was employed to assess FDG uptake in human α-syn (A53T) overexpressing mice. Levels of lnc HOTAIRM1 and miR-223-3p were detected via qRT-PCR. Flow cytometry was deployed to assay cell apoptosis. Here, we found that AVE0991 improved behaviour disorders and decreased α-syn expression in the substantia nigra of mice with Parkinson's disease. AVE0991 inhibited the apoptosis of dopaminergic neurons overexpressing hα-syn (A53T) via lncRNA HOTAIRM1. MiR-223-3p binds to HOTAIRM1 as a ceRNA and directly targets α-syn. Moreover, miR-223-3p level in peripheral blood was found negatively correlated with the α-syn. Our present study shows that the angiotensin-(1-7) analogue AVE0991 targeted at the HOTAIRM1/miR-223-3p axis to degrade α-synuclein in PD mice, and showed neuroprotection in vitro., (© 2024. The Author(s).)

Abstract Background Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1), which displays a distinct long noncoding RNA (lncRNA) expression profile, has been defined as a unique subgroup in the new classification of myeloid neoplasms. However, the biological roles of key lncRNAs in the development of NPM1-mutated AML are currently unclear. Here, we aimed to investigate the functional and mechanistic roles of the lncRNA HOTAIRM1 in NPM1-mutated AML. Methods The expression of HOTAIRM1 was analyzed with a public database and further determined by qRT-PCR in NPM1-mutated AML samples and cell lines. The cause of upregulated HOTAIRM1 expression was investigated by luciferase reporter, chromatin immunoprecipitation and ubiquitination assays. The functional role of HOTAIRM1 in autophagy and proliferation was evaluated using western blot analysis, immunofluorescence staining, a Cell Counting Kit-8 (CCK-8) assay, a 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, flow cytometric analyses and animal studies. The action mechanism of HOTAIRM1 was explored through RNA fluorescence in situ hybridization, RNA pulldown and RNA immunoprecipitation assays. Results HOTAIRM1 was highly expressed in NPM1-mutated AML. High HOTAIRM1 expression was induced in part by mutant NPM1 via KLF5-dependent transcriptional regulation. Importantly, HOTAIRM1 promoted autophagy and proliferation both in vitro and in vivo. Mechanistic investigations demonstrated that nuclear HOTAIRM1 promoted EGR1 degradation by serving as a scaffold to facilitate MDM2-EGR1 complex formation, while cytoplasmic HOTAIRM1 acted as a sponge for miR-152-3p to increase ULK3 expression. Conclusions Taken together, our findings identify two oncogenic regulatory axes in NPM1-mutated AML centered on HOTAIRM1: one involving EGR1 and MDM2 in the nucleus and the other involving the miR-152-3p/ULK3 axis in the cytoplasm. Our study indicates that HOTAIRM1 may be a promising therapeutic target for this distinct leukemia subtype.

Sepsis-induced myeloid-derived suppressor cells (MDSCs) increase mortality risk. We previously identified that long non-coding RNA Hotairm1 supports myeloid precursor shifts to Gr1+CD11b+ MDSCs during mouse sepsis. A major unanswered question is what molecular processes control Hotairm1 expression. In this study, we found by a genetic deletion that a specific PU.1-binding site is indispensable in controlling Hotairm1 transcription. We then identified H3K4me3 and H3K27me3 at the PU.1 site on the Hotairm1 promoter. Controlling an epigenetic switch of Hotairm1 transcription by PU.1 was histone KDM6A demethylase for H3K27me3 that derepressed its transcription with possible contributions from Ezh2 methyltransferase for H3K27me3. KDM6A knockdown in MDSCs increased H3K27me3, decreased H3K4me3, and inhibited Hotairm1 transcription activation by PU.1. These results enlighten clinical translation research of PU.1 epigenetic regulation as a potential sepsis immune-checkpoint treatment site.

Asthma is a heterogeneous entity encompassing distinct endotypes and varying phenotypes, characterized by common clinical manifestations, such as shortness of breath, wheezing, and variable airflow obstruction. Two major asthma endotypes based on molecular patterns are described: type 2 endotype (allergic-asthma) and T2 low endotype (obesity-related asthma). Long noncoding RNAs (lncRNAs) are transcripts of more than 200 nucleotides in length, currently involved in many diverse biological functions, such as chromatin remodeling, gene transcription, protein transport, and microRNA processing. Despite the efforts to accurately classify and discriminate all the asthma endotypes and phenotypes, if long noncoding RNAs could play a role as biomarkers in allergic asthmatic and adolescent obesity-related asthma, adolescents remain unknown. To compare expression levels of lncRNAs: HOTAIRM1, OIP5-AS1, MZF1-AS1, and GAS5 from whole blood of Healthy Adolescents (HA), Obese adolescents (O), allergic asthmatic adolescents (AA) and Obesity-related asthma adolescents (OA). We measured and compared expression levels from the whole blood of the groups mentioned above through RT-q-PCR. We found differentially expressed levels of these lncRNAs between the groups of interest. In addition, we found a discriminative value of previously mentioned lncRNAs between studied groups. Finally, we generated an interaction network through bioinformatics. Expression levels of OIP5-AS1, MZF1-AS1, HOTAIRM1, and GAS5 in whole blood from the healthy adolescent population, obese adolescents, allergic asthma adolescents, and obesity-related asthma adolescents are differently expressed. Moreover, these lncRNAs could act as molecular biomarkers that help to discriminate between all studied groups, probably through molecular mechanisms with several genes and miRNAs implicated.

In cancer cells, a gain of stemness may have profound implications for tumor initiation, aggressiveness, and clinical outcome. However, the molecular mechanisms underlying the self-renewal maintenance of cancer stem-like cells (CSCs) remain elusive. Here, based on analysis of transcriptome sequencing, we identified a long noncoding RNA (lncRNA) named HotairM1, which is weakly expressed in human colorectal carcinoma and uveal melanoma, and a much lower expression in corresponding CSCs. Our results showed that HotairM1 depletion could promote CSC self-renewal and tumor propagation. Mechanistically, HotairM1 recruit EZH2 and SUZ12 to the promoter of its target gene HOXA1, leading to histone H3K27 trimethylation and epigenetic silencing of HOXA1. The silence of HOXA1 subsequently induces the H3K27 acetylation at the enhancer site of Nanog gene to upregulate its expression. The enrichment of Nanog could further inhibit HOXA1 expression, forming a reciprocal regulation loop augmenting the stemness maintaining effect. In summary, our results revealed a lncRNA-based regulatory loop that sustains self-renewal of CSCs, which highlights the critical role of HotairM1 in CSC development through the HOXA1-Nanog signaling loop.

Myeloid-derived suppressor cells (MDSCs) prolong sepsis by promoting immunosuppression. We reported that sepsis MDSC development requires long non-coding RNA Hotairm1 interactions with S100A9. Using a mouse model that simulates the immunobiology of sepsis, we find that histone demethylase KDM6A promotes Hotairm1 transcription by demethylating transcription repression H3K27me3 histone mark. We show that chemical targeting of KDM6A by GSK-J4 represses Hotairm1 transcription, which coincides with decreases in transcription activation H3K4me3 histone mark and transcription factor PU.1 binding to the Hotairm1 promoter. We further show that immunosuppressive IL-10 cytokine promotes KDM6A binding at the Hotairm1 promoter. IL-10 knockdown repletes H3K27me3 and reduces Hotairm1 transcription. GSK-J4 treatment also relocalizes nuclear S100A9 protein to the cytosol. To support translation to human sepsis, we demonstrate that inhibiting H3K27me3 demethylation by KDM6A ex vivo in MDSCs from patients with protracted sepsis decreases Hotairm1 transcription. These findings suggest that epigenetic targeting of MDSCs in human sepsis might resolve post-sepsis immunosuppression and improve sepsis survival. [ABSTRACT FROM AUTHOR]

Background ‒ Propofol, an intravenous sedative-hypnotic agent, is demonstrated to have antioxidant properties. The purpose of this study is to investigate the functional roles of propofol in neuroblastoma cells. Methods ‒ The proliferation and apoptosis were assessed by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide (MTT), EdU, and flow cytometry assays, respectively. The protein expression level was quantified by western blot assay. Inflammation and oxidative stress were determined by measuring the release of inflammatory factors, along with intracellular reactive oxygen species (ROS), lactate dehydrogenase (LDH), malondialdehyde (MDA), and superoxide dismutase (SOD) levels. The real-time quantitative polymerase chain reaction (RT-qPCR) was conducted to assess the expression levels of HOXA transcript antisense RNA, myeloid-specific 1 (HOTAIRM1), and miR-519a-3p in cells. The interaction relationship between HOTAIRM1 and miR-519a-3p was confirmed by dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays. Results ‒ Treatment with MPP+ has been observed to induce apoptosis, oxidative stress, and inflammation in neuroblastoma cells, which were abolished by propofol or silencing of HOTAIRM1. Importantly, the increase of HOTAIRM1 and the decrease of miR-519a-3p caused by MPP+ were reversed by propofol in neuroblastoma cells. In addition, miR-519a-3p was a target of HOTAIRM1, and inhibition of miR-519a-3p abolished HOTAIRM1 silencing-induced effects on neuroblastoma cells. Moreover, functional experiments revealed that propofol might weaken MPP+-induced apoptosis, oxidative stress, and inflammation by regulating the HOTAIRM1/miR-519a-3p axis. Conclusion ‒ Propofol inhibited oxidative stress and inflammation in MPP+-induced neuroblastoma cells by targeting the HOTAIRM1/miR-519a-3p axis, implying the potential protective function of propofol against oxidative damage. [ABSTRACT FROM AUTHOR]

Ovarian cancer is one of the most heterogeneous malignancies in the field of gynecologic oncology. Deregulation of long noncoding RNAs (lncRNAs) is implicated in carcinogenesis. Therefore, the present study was conducted to investigate the possible role of lncRNA of HOXA transcript antisense intergenic RNA myeloid‐specific 1(HOTAIRM1) in progression of SKOV3 cells in ovarian cancer and also its underlying molecular mechanisms. HOTAIRM1 expression level will be measured by real‐time polymerase chain reaction (PCR) in SKOV3 cells. For determining the effect of HOTAIRM1 silencing on progression of SKOV3 cells, siHOTAIRM1 will be designed and transfected into cells using a liposomal approach. MTT and trypan blue assays will be used to determine the effect of HOTAIRM1 silencing on cell proliferation. Apoptosis of the cells will be detected by flow cytometry. Furthermore, expressions of apoptosis‐related genes and Wnt pathway‐related proteins and genes will be analyzed by Western blot and real‐time PCR. HOTAIRM1 was overexpressed in SKOV3 cells. Silencing of HOTAIRM1 alleviated cell proliferation, and increased cell apoptosis of SKOV3 cells. Moreover, siHOTAIRM1 significantly increased expression of pro‐apoptotic agents, such as Bad and Bax, while it decreased expressions of Bid and Bcl‐2 (anti‐apoptotic agents). Also, silencing of HOTAIRM1 resulted in a suppressed expression of Wnt pathway‐related proteins and also expression of its downstream target gene, matrix metalloproteinase 9(MMP9). Our findings provided new insights into function of lncRNA of HOTAIRM1 in progression of ovarian cancer by modulating Wnt pathway and its downstream target gene, MMP9. [ABSTRACT FROM AUTHOR]

Tian-jun Chen,1,* Fei Gao,1,2,* Tian Yang,1 Hong Li,1 Yang Li,1 Hui Ren,1 Ming-wei Chen1 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, People’s Republic of China; 2Ultrasound Department, Huashan Central Hospital of Xi’an, Xi’an, Shaanxi 710043, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ming-wei ChenDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277, Yanta West Road, Xi’an, Shaanxi, People’s Republic of ChinaTel +86 29-85323888Email wosyishen66@163.comBackground: Lung adenocarcinoma (ADC) is a major form of lung cancer, which is a main cause of global cancer-related death in male and female patients. LncRNAs are implicated in tumor development. However, the functions and mechanisms of the LncRNA HOTAIRM1 in ADC are not known.Materials and Methods: Here, the downregulated HOTAIRM1 in ADC was selected by TCGA analysis. Subsequently, qRT-PCR, CCK-8, EdU, cell apoptosis, cell cycle and cell invasion assays were utilized for evaluating the roles of HOTAIRM1 in ADC. Finally, we explored the mechanism of HOTAIRM1 in ADC.Results: HOTAIRM1 expression was considerably decreased in ADC tissues. The knockdown of HOTAIRM1 promoted the cell cycle, growth, and invasion of ADC. Moreover, HOTAIRM1 competitively bound miR-498 to regulate the expression of WWOX.Conclusion: HOTAIRM1 suppressed the proliferation and invasion of ADC cells via the modulation of miR-498/WWOX axis. This finding suggested that it might be clinically valuable as a biomarker for ADC. Furthermore, the findings suggest LncRNA HOTAIRM1 as a candidate therapeutic target in ADC.Keywords: HOTAIRM1, lung adenocarcinoma, miR-498, WWOX, cell proliferation

Myeloid-derived suppressor cells (MDSCs) prolong sepsis by promoting immunosuppression. We reported that sepsis MDSC development requires long non-coding RNA Hotairm1 interactions with S100A9. Using a mouse model that simulates the immunobiology of sepsis, we find that histone demethylase KDM6A promotes Hotairm1 transcription by demethylating transcription repression H3K27me3 histone mark. We show that chemical targeting of KDM6A by GSK-J4 represses Hotairm1 transcription, which coincides with decreases in transcription activation H3K4me3 histone mark and transcription factor PU.1 binding to the Hotairm1 promoter. We further show that immunosuppressive IL-10 cytokine promotes KDM6A binding at the Hotairm1 promoter. IL-10 knockdown repletes H3K27me3 and reduces Hotairm1 transcription. GSK-J4 treatment also relocalizes nuclear S100A9 protein to the cytosol. To support translation to human sepsis, we demonstrate that inhibiting H3K27me3 demethylation by KDM6A ex vivo in MDSCs from patients with protracted sepsis decreases Hotairm1 transcription. These findings suggest that epigenetic targeting of MDSCs in human sepsis might resolve post-sepsis immunosuppression and improve sepsis survival.

Background: Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1), which displays a distinct long noncoding RNA (lncRNA) expression profile, has been defined as a unique subgroup in the new classification of myeloid neoplasms. However, the biological roles of key lncRNAs in the development of NPM1-mutated AML are currently unclear. Here, we aimed to investigate the functional and mechanistic roles of the lncRNA HOTAIRM1 in NPM1-mutated AML. Methods: The expression of HOTAIRM1 was analyzed with a public database and further determined by qRT-PCR in NPM1-mutated AML samples and cell lines. The cause of upregulated HOTAIRM1 expression was investigated by luciferase reporter, chromatin immunoprecipitation and ubiquitination assays. The functional role of HOTAIRM1 in autophagy and proliferation was evaluated using western blot analysis, immunofluorescence staining, a Cell Counting Kit-8 (CCK-8) assay, a 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, flow cytometric analyses and animal studies. The action mechanism of HOTAIRM1 was explored through RNA fluorescence in situ hybridization, RNA pulldown and RNA immunoprecipitation assays. Results: HOTAIRM1 was highly expressed in NPM1-mutated AML. High HOTAIRM1 expression was induced in part by mutant NPM1 via KLF5-dependent transcriptional regulation. Importantly, HOTAIRM1 promoted autophagy and proliferation both in vitro and in vivo. Mechanistic investigations demonstrated that nuclear HOTAIRM1 promoted EGR1 degradation by serving as a scaffold to facilitate MDM2-EGR1 complex formation, while cytoplasmic HOTAIRM1 acted as a sponge for miR-152-3p to increase ULK3 expression. Conclusions: Taken together, our findings identify two oncogenic regulatory axes in NPM1-mutated AML centered on HOTAIRM1: one involving EGR1 and MDM2 in the nucleus and the other involving the miR-152-3p/ULK3 axis in the cytoplasm. Our study indicates that HOTAIRM1 may be a promising therapeutic target for this distinct leukemia subtype. [ABSTRACT FROM AUTHOR]

Abstract Background Non-small cell lung cancer (NSCLC) as the most frequent type of lung cancer is associated with extensive mortality. Researchers have studied the suitability of several molecules as biomarkers for early detection of this cancer. Long non-coding RNAs (lncRNAs) as the main regulators of gene expression have also been assessed in this regard. Methods In the present study, we compared expression level of Fas-antisense 1 (FAS-AS1), Growth Arrest Specific 5 (GAS5), PVT1, Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1), taurine upregulated gene 1 (TUG1) and TNFα and hnRNPL related immunoregulatory LincRNA (THRIL) in 32 NSCLC samples and their corresponding adjacent non-cancerous tissues (ANCTs). Results NEAT1 has been significantly over-expressed in NSCLC tissues obtained from male subjects compared with the corresponding ANCTs (Relative expression (REx) = 3.022, P = 0.019) but not in female subjects (P = 0.975). FAS-AS1 was significantly down-regulated in NSCLC tissues obtained from both males and females subjects compared with the corresponding ANCTs (REx = − 4.12 and − 3.14, P = 0.015 and 0.033 respectively). TUG1, GAS5, THRIL and HOTAIRM1 were significantly down-regulated in tumoral tissues obtained from male subjects compared with the corresponding ANCTs. Conclusions The observed dysregulation of these lncRNAs in NSCLC tissues compared with the corresponding ANCTs warrants future studies to confirm the results of the current study in larger sample sizes to elaborate their role as cancer biomarkers.

Recent studies have reported that cancer associated fibroblasts (CAFs) and glioma stem-like cells (GSCs) played active roles in glioma progression in tumor microenvironment (TME). Long non-coding RNAs (lncRNAs) have been found to be closely associated with glioma development in recent years, however, their molecular regulatory mechanisms on CAFs in GSCs remodeled TME kept largely unelucidated. Our study found that GSCs could induce malignant transformation of fibroblasts (t-FBs) based on dual-color fluorescence tracing orthotopic model. Associated with poor prognosis, Lnc HOXA transcript antisense RNA, myeloid-specific 1 (HOTAIRM1) was highly expressed in high-grade gliomas and t-FBs. Depleting HOTAIRM1 inhibited the proliferation, invasion, migration, and even tumorigenicity of t-FB. Conversely, overexpression of HOTAIRM1 promoted malignancy phenotype of t-FB. Mechanistically, HOTAIRM1 directly bound with miR-133b-3p, and negatively regulated the latter. MiR-133b-3p partly decreased the promotion effect of HOTAIRM1 on t-FBs. Furthermore, transforming growth factor-β (TGFβ) was verified to be a direct target of miR-133b-3p. HOTAIRM1 can modulate TGFβ via competing with miR-133b-3p. Collectively, HOTAIRM1/miR-133b-3p/TGFβ axis was involved in modulating t-FBs malignancy in TME remodeled by GSCs, which had the potential to serve as a target against gliomas.

Recent studies have reported that cancer associated fibroblasts (CAFs) and glioma stem-like cells (GSCs) played active roles in glioma progression in tumor microenvironment (TME). Long non-coding RNAs (lncRNAs) have been found to be closely associated with glioma development in recent years, however, their molecular regulatory mechanisms on CAFs in GSCs remodeled TME kept largely unelucidated. Our study found that GSCs could induce malignant transformation of fibroblasts (t-FBs) based on dual-color fluorescence tracing orthotopic model. Associated with poor prognosis, Lnc HOXA transcript antisense RNA, myeloid-specific 1 (HOTAIRM1) was highly expressed in high-grade gliomas and t-FBs. Depleting HOTAIRM1 inhibited the proliferation, invasion, migration, and even tumorigenicity of t-FB. Conversely, overexpression of HOTAIRM1 promoted malignancy phenotype of t-FB. Mechanistically, HOTAIRM1 directly bound with miR-133b-3p, and negatively regulated the latter. MiR-133b-3p partly decreased the promotion effect of HOTAIRM1 on t-FBs. Furthermore, transforming growth factor-β (TGFβ) was verified to be a direct target of miR-133b-3p. HOTAIRM1 can modulate TGFβ via competing with miR-133b-3p. Collectively, HOTAIRM1/miR-133b-3p/TGFβ axis was involved in modulating t-FBs malignancy in TME remodeled by GSCs, which had the potential to serve as a target against gliomas. [ABSTRACT FROM AUTHOR]

Emerging evidence is indicating the importance of hundreds of long noncoding RNAs (lncRNAs) in the occurrence and progression of different malignancies such as prostate cancer (PCa). This study investigated the possible role of HOX transcript antisense intergenic RNA myeloid‐specific 1 (HOTAIRM1) in the progression of tumorigenesis of PC3 as PCa cell line. RT‐qPCR was used to measure HOTAIRM1 expression levels in PC3 and RWPE‐1 cell lines. To detect the effect of HOTAIRM1 in the progression of PCa, HOTAIRM1 was silenced on PC3 cells with specific siRNA and transfected into cells using a liposomal approach. Using MTT assay, the effects of si‐HOTAIRM1 on cell viability and proliferation were evaluated. Cell apoptosis was analysed using flow cytometry and Wnt pathway‐related proteins by Western blot. HOTAIRM1 was overexpressed in PC3 cells compared with RWPE‐1 cells. Reducing HOTAIRM1 alleviated cell proliferation and increased apoptosis of PC3 cells so that the expression of pro‐apoptotic agents such as Bad and Bax was significantly increased, while that of Bid and Bcl‐2 (anti‐apoptotic) was decreased. Furthermore, HOTAIRM1 silencing suppressed the Wnt pathway. Overall, HOTAIRM1 silencing in PC3 cells inhibited the proliferative ability and promoted the apoptosis of PCa cells by suppressing the Wnt pathway, thereby inhibiting the progression of PCa. [ABSTRACT FROM AUTHOR]

Background: Non-small cell lung cancer (NSCLC) is a major contributor of cancer-related mortality. Long non-coding RNAs (lncRNAs) are indicated to participate in the pathogenesis of NSCLC. Objective: In this research, the effects of lncRNA HOXA transcript antisense RNA, myeloid-specific 1 (HOTAIRM1) on NSCLC progression and underlying mechanism were revealed. Methods: The expression levels of HOTAIRM1 and microRNA-498 (miR-498) were detected by quantitative real time polymerase chain reaction (qRT-PCR) in NSCLC tissues, cells or exosomes. The protein expression of CD63, CD81, hexokinase 2 (HK2) and ATP binding cassette subfamily E member 1 (ABCE1) was determined by western blot. Cell viability, apoptosis, migration and invasion were investigated by cell counting kit-8 (CCK-8), flow cytometry, transwell migration and invasion assays, respectively. Cell glycolysis metabolism was revealed by glucose uptake and lactate production assays and western blot analysis. The binding relationship between miR-498 and HOTAIRM1 or ABCE1 was predicted by DIANA-LncBase v2 and starBase online database, and identified by dual-luciferase reporter assay. The effects of HOTAIRM1 on NSCLC growth in vivo were revealed by in vivo tumor formation assay. Results: HOTAIRM1 expression was dramatically upregulated, whereas miR-498 expression was significantly downregulated in NSCLC tissues cells or exosomes as compared to control groups. Mechanistically, HOTAIRM1 knockdown repressed cell viability, migration, invasion and glycolysis metabolism, whereas induced cell apoptosis in NSCLC; however, miR-498 inhibitor hindered these effects. Functionally, HOTAIRM1 functioned as a sponge of miR-498 and miR-498 targeted ABCE1. In addition, HOTAIRM1 silencing inhibited NSCLC growth in vivo by downregulating ABCE1 and upregulating miR-498 expression. Conclusions: HOTAIRM1 knockdown repressed cell glycolysis metabolism and tumor development by reducing ABCE1 expression through sponging miR-498 in NSCLC, which provided a theoretical basis for further studying NSCLC progression. [ABSTRACT FROM AUTHOR]

• Increasing researches have reported that HOTAIRM1 was abnormally expressed and could be an independent predictor of poor prognosis in diverse carcinomas. • The abnormal expression, biological function and effect mechanism of HOTAIRM1 in cancers were reviewed in this manuscript. Long noncoding RNAs (lncRNAs) are a group of RNAs over 200 nucleotides in length involved in diverse processes in tumor cells including proliferation, invasion and apoptosis. Given these facts, it is hardly accidental that variations in the expression of some lncRNAs have been found to be closely related to carcinogenesis and tumor growth and metastasis. HOTAIRM1, first discovered as an important factor for granulocytic differentiation in NB4 promyelocytic leukemia, has been shown to be a salient cancer-related lncRNA abnormally expressed in a variety of tumors. In this review, we summarize current evidence on the critical role of HOTAIRM1 in human malignancy, its potential mechanism of action and future use in the development of effective therapeutics. [ABSTRACT FROM AUTHOR]

Abstract Background Glioblastoma multiforme (GBM) is the common primary brain tumor classified the most malignant glioma. Long non-coding RNAs (LncRNAs) are important epigenetic regulators with critical roles in cancer initiation and progression. LncRNA HOTAIRM1 transcribes from the antisense strand of HOXA gene cluster which locus in chromosome 7p15.2. Recent studies have shown that HOTAIRM1 is involved in acute myeloid leukemia and colorectal cancer. Here we sought to investigate the role of HOTAIRM1 in GBM and explore its mechanisms of action. Methods The expressions of HOTAIRM1 and HOXA1 in GBM tissues and cells were determined by qRT-PCR, and the association between HOTAIRM1, HOXA1 transcription and tumor grade were analyzed. The biological function of HOTAIRM1 in GBM was evaluated both in vitro and in vivo. Chromatin immunoprecipitation (ChIP) assay and quantitative Sequenom MassARRAY methylation analysis were performed to explore whether HOTAIRM1 could regulate histone and DNA modification status of the HOXA1 gene transcription start sites (TSS) and activate its transcription. ChIP and RNA-ChIP were further performed to determine the molecular mechanism of HOTAIRM1 in epigenetic regulation of the HOXA1 gene. Results HOTAIRM1 was abnormally up-regulated in GBM tissues and cells, and this up-regulation was correlated with grade malignancy in glioma patients. HOTAIRM1 silencing caused tumor suppressive effects via inhibiting cell proliferation, migration and invasion, and inducing cell apoptosis. In vivo experiments showed knockdown of HOTAIRM1 lessened the tumor growth. Additionally, HOTAIRM1 action as regulating the expression of the HOXA1 gene. HOXA1, as an oncogene, it’s expression levels were markedly elevated in GBM tissues and cell lines. Mechanistically, HOTAIRM1 mediated demethylation of histone H3K9 and H3K27 and reduced DNA methylation levels by sequester epigenetic modifiers G9a and EZH2, which are H3K9me2 and H3K27me3 specific histone methyltransferases, and DNA methyltransferases (DnmTs) away from the TSS of HOXA1 gene. Conclusions We investigated the potential role of HOTAIRM1 to promote GBM cell proliferation, migration, invasion and inhibit cell apoptosis by epigenetic regulation of HOXA1 gene that can be targeted simultaneously to effectively treat GBM, thus putting forward a promising strategy for GBM treatment. Meanwhile, this finding provides an example of transcriptional control over the chromatin state of gene and may help explain the role of lncRNAs within the HOXA gene cluster.

Abstract This study is aimed to explore the regulatory effect of lncRNA HOTAIR/miR‐148a/DLGAP1 axis on head and neck tumor (HNT) cell growth, cell mobility, and invasiveness. HOTAIRM1, miR‐148a, and DLGAP1 level in HNT tissues and adjacent normal tissues were measured by qRT‐PCR. Cell Counting Kit‐8 (CCK‐8) and Transwell (migration and invasion) assay were used to survey the influence of HOTAIRM1, miR‐148a, and DLGAP1 on Fadu cells. Nude mouse xenograft was utilized to validate the influence of HOTAIRM1 in vivo. Dual‐luciferase reporter assay confirms the relationship between HOTAIRM1 and miR‐148a, miR‐148a, and DLGAP1. The expression level of HOTAIRM1 was downregulated in human HNT tissues and cells. Overexpression of HOTAIRM1 significantly moderated Fadu cells proliferation, apoptosis, migration, and invasion in vitro and impaired the tumorigenesis in vivo. The expression level of miR‐148a was upregulated in human HNT tissue compared to the adjacent tissues. We identified that miR‐148a was a target of HOTAIRM1 and its expression levels were reduced by HOTAIRM1. Transfection of miR‐148a mimics increased proliferation, migration, and invasion of Fadu cells. DLGAP1 was identified as a novel target of miR‐148a and its expression level was promoted by either HOTAIRM1 overexpression or miR‐148a knockdown. Overexpression of DLGAP1 also facilitated the cell viability and metastasis of Fadu cells. HOTAIRM1 was confirmed as a tumor suppressor via sponging miR‐148a and promote the expression of DLGAP1, which could be regarded as an important target for the prevention and treatment of HNT.

• HOTAIRM1 first increased and then decreased with the time of HQ treatment on TK6 cells or workers exposed to benzene. • DNA hypermethylation induced by DNMT3b involves in the silence of HOTAIRM1 expression in HQ-MT cells. • HOTAIRM1 expressionwas restored by reducing methylation levels of its promoter in HQ-MT cells treated with 5-AzaC or TSA. • Knockout of DNMT3b increased expression of HOTAIRM1 and HOTAIRM1 promoter hypomethylation in HQ-MT cells. Benzene exposure is a risk factor of acute myeloid leukemia (AML), during such carcinogenesis long non-coding RNAs (lncRNAs) are important epigenetic regulators. HOTAIRM1 (HOXA transcript antisense RNA, myeloid-specific 1) plays an indispensable role in the development of AML. Hydroquinone (HQ) is one major metabolite of benzene and its ideal replacement in toxicology research. But the influence of benzene or HQ on HOTAIRM1 expression in AML associated pathway is still unclear. In the TK6 cells with short-term exposure to HQ (HQ-ST cells) or long term HQ exposure induced malignant transformed TK6 cells (HQ-MT cells), the relationship between DNMT3b and HOTAIRM1 was explored. Comparing to counterparts, HOTAIRM1 expression was increased firstly and then decreased in HQ-ST cells, and definitely decreased in HQ-MT cells; while the expression change tendency of DNMT3b was in contrast to that of HOTAIRM1. Moreover, the average HOTAIRM1 expression of 17 paired workers being exposed to benzene within 1.5 years was increased, but that of the remaining 92 paired workers with longer exposure time was decreased. Furthermore, in 5-AzaC (DNA methyltransferase inhibitor) or TSA (histone deacetylation inhibitor) treated HQ-MT cells, the expression of HOTAIRM1 was restored by reduced DNA promoter methylation levels. HQ-MT cells with DNMT3b knockout by CRISPR/Cas9 displayed the promoter hypomethylation and the increase of HOTAIRM1, also confirmed in benzene exposure workers. These suggest that long term exposure to HQ or benzene might induce the increase of DNMT3b expression and the promoter hypermethylation to silence the expression of HOTAIRM1, a possible tumor-suppressor in the AML associated carcinogenesis pathway. [ABSTRACT FROM AUTHOR]

Noncoding RNAs regulate transcription of gene expression and play an important role in the pathogenesis of glioblastomas. These tumors are heterogeneous with some glioma stem cells (GSCs) that are highly tumorigenic subpopulations of cells contributing to recurrence and treatment resistance. In this study, GSCs were established by neurosphere cultures of primary glioblastoma cells and validated by the expression of GSC marker CD133. The expression of the long noncoding RNA HOTAIRM1 was detected using real-time quantitative reverse transcription PCR (qRT-PCR). The role of HOTAIRM1 in the proliferation, apoptosis, stemness, and tumorigenicity of GSCs was investigated by soft agar colony formation, flow cytometry, TUNEL analysis, sphere formation, and in vivo xenograft models through silencing of HOTAIRM1. The expression of HOTAIRM1 and the neighboring HOX genes were analyzed by qRT-PCR in different grades of gliomas and nontumor tissues. We found that HOTAIRM1 is significantly elevated in GSCs. The silencing of HOTAIRM1 significantly impairs the proliferation, apoptosis, self-renewal, tumorigenesis of GSCs. In addition, HOTAIRM1 is significantly upregulated in gliomas and associated with tumor grade and patient survival. HOTAIRM1 neighboring genes, HOXA1, HOXA2, and HOXA3, are also significantly upregulated in gliomas and correlate with the expression of HOTAIRM1. Among them, HOXA2 and HOXA3 were identified as being upregulated in GSCs and contributed to the self-renewal of these stem cells. Taken together, our results demonstrate that HOTAIRM1 plays a critical role in the self-renewal of GSCs. These data also suggest that overexpression of HOTAIRM1 can be a negative prognostic factor for patient survival in malignant glioma and may be a promising potential therapeutic target. [ABSTRACT FROM AUTHOR]

The long noncoding RNA HOTAIRM1 reportedly plays important roles in acute myeloid leukemia, gastric cancer and colorectal cancer. Here, we analyzed potential function of HOTAIRM1 in glioma and asked whether it participates in long-range chromatin interactions. We monitored expression of HOTAIRM1 in glioma tissues and correlated levels with patient survival using the TCGA dataset. HOTAIRM1 was highly expressed in glioma tissue, with high levels associated with shortened patient survival time. We then suppressed HOTAIRM1 activity in the human glioblastoma U251 line using CRISPR-cas9 to knock in a truncating polyA fragment. Reporter analysis of these and control cells confirmed that the HOTAIRM1 locus serves as an active enhancer. We then performed Capture-C analysis to identify target genes of that locus and applied RNA antisense purification to assess chromatin interactions between the HOTAIRM1 locus and HOXA cluster genes. HOTAIRM1 knockdown in glioma cells decreased proliferation and reduced expression of HOXA cluster genes. HOTAIRM1 regulates long-range interactions between the HOTAIRM1 locus and HOXA genes. Our work suggests a new mechanism by which HOTAIRM1 regulates glioma progression by regulating high-order chromatin structure and could suggest novel therapeutic targets to treat an intractable cancer. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) have fundamental roles in cell migration, proliferation, invasion and metastasis. In the current study, we evaluated expression of a panel of lncRNAs in bladder cancer tissues, adjacent non-cancerous tissues (ANCTs) and normal bladder tissues to evaluate their diagnostic power. PV1 was down-regulated in tumor tissues compared with both ANCTs and normal controls (Expression ratios of 0.48 and 0.14; P values of 0.4 and <0.001 respectively). HOTAIR , NEAT1 , TUG1 and FAS-AS1 were significantly down-regulated in tumor tissues compared with normal controls (Expression ratios of 0.4, 0.68, 0.54 and 0.11; P values of 0.04, 0.02, 0.02 and <0.001 respectively). Combination of transcript levels of seven lncRNAs improved both sensitivity and specificity values to 100%. The current study shows dysregulation of lncRNAs in bladder cancer and implies their role as diagnostic markers in this malignancy. • We evaluated expression of a panel of lncRNAs in bladder cancer tissues, adjacent non-cancerous tissues (ANCTs) and normal bladder tissues to evaluate their diagnostic power. • HOTAIR , NEAT1 , TUG1 and FAS-AS1 were significantly down-regulated in tumor tissues compared with normal controls. • GHET1 and HOTAIRM1 were significantly up-regulated in tumor tissues compared with normal controls. • Combination of transcript levels of seven lncRNAs improved both sensitivity and specificity values to 100%. • The current study shows dys-regulation of lncRNAs in bladder cancer and highlights their role as diagnostic markers in this malignancy. [ABSTRACT FROM AUTHOR]

Background: Long non-coding RNA (lncRNA) microarray screening previously identified that HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) was significantly upregulated in type I endometrial cancer (EC). The present study aimed to determine the potential role of HOTAIRM1 and its sense transcript HOXA1 in the development and progression of type I EC. Methods: We detected the expression levels of HOTAIRM1 and HOXA1 in type I EC tissues by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting and analyzed associated clinical data. Gain- or loss-of-function experiments were used to investigate the biological function of HOTAIRM1 and HOXA1 in type I EC, both in vitro and in vivo. Results: The expression levels of HOTAIRM1 and HOXA1 were significantly upregulated in type I EC tissues. Furthermore, the expression of HOTAIRM1 and HOXA1 were both significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. The expression of HOTAIRM1 was significantly correlated with that of HOXA1. Knockdown of HOTAIRM1 significantly inhibited cell proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) in vitro, while the over-expression of HOTAIRM1 led to the opposite effects. Moreover, we identified that HOTAIRM1 acts as a regulator for the expression of the HOXA1 gene in type I EC cells. As an oncogene, HOXA1 silencing also caused suppressive effects on tumors by inhibiting cell proliferation, migration and invasion. In addition, we also confirmed the role of HOTAIRM1 and HOXA1 in promoting tumor growth in vivo. Conclusion: Our findings are the first to identify that HOTAIRM1 functions as an oncogene to promote cell proliferation, migration and invasion by regulating HOXA1 in type I EC. Therefore, the HOTAIRM1/HOXA1 axis is a novel potential prognostic biomarker and new potential therapeutic target for type I EC. [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5-FU)-based chemotherapy has always been the first-line treatment of colorectal cancer (CRC). However, the occurrence of clinical 5-FU resistance is a major reason for CRC therapy failure. This study intended to explore the possible role of long non-coding RNA HOTAIRM1 (HOTAIRM1) in the pathogenesis of 5-FU resistant CRC and its underlying mechanism. Our data showed that HOTAIRM1 was downregulated in CRC tissues and cell lines (HCT116 and SW480), and even lower in 5-FU resistant CRC tissues and cell lines (HCT116/5-FU and SW480/5-FU). In vitro, effects of HOTAIRM1 dysregulation in 5-FU resistant CRC cells were investigated and its overexpression could reduce cell viability, invasion, migration, and multi-drug resistance as evidenced by MTT assay, Transwell assay, epithelial-mesenchymal transition (EMT), and western blot analyzing expression of drug-resistant genes MRP1 and MDR1, respectively. Mechanically, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) identified that HOTAIRM1 and B-cell translocation gene 3 (BTG3) were target genes of miR-17-5p. Moreover, miR-17-5p was upregulated and BTG3 was downregulated in HCT116/5-FU and SW480/5-FU cells. Silencing of miR-17-5p showed suppressive role on cell viability, invasion, migration, and multi-drug resistance in HCT116/5-FU and SW480/5-FU cells, which could be abolished by HOTAIRM1 knockdown. Similarly, ectopic expression of miR-17-5p reversed BTG3-mediated inhibition on cell viability, invasion, migration, and multi-drug resistance. In vivo, the tumorigenesis of HCT116/5-FU cells when highly expressed HOTAIRM1 by lentivirus infection was inhibited through downregulating miR-17-5p and upregulating BTG3. In conclusion, HOTAIRM1 might act as a tumor-suppressor in 5-FU resistant CRC cells in vitro and in vivo through downregulating miR-17-5p/BTG3 pathway and inhibiting multi-drug resistance.

Mesenchymal stem cells (MSCs) have potential ability to differentiate into osteocytes in response to in vitro specific induction. However, the molecular basis underlying this biological process remains largely unclear. In this study, we identify lncRNA HOTAIRM1 as a critical regulator to promote osteogenesis of MSCs. Loss of HOTAIRM1 significantly inhibits the calcium deposition and alkaline phosphatase activity of MSCs. Mechanistically, we find that HOTAIRM1 positively modulates the activity of JNK and c‐Jun, both of which are widely accepted as crucial regulators of osteogenic differentiation. More importantly, c‐Jun is found to be functionally involved in the regulation of RUNX2 expression, a master transcription factor of osteogenesis. In detail, c‐Jun can help recruit the acetyltransferase p300 to RUNX2 promoter, facilitating acetylation of histone 3 at K27 site, therefore epigenetically activating RUNX2 gene transcription. In summary, this study highlights the functional importance of HOTAIRM1 in regulation of osteogenesis, and we characterize HOTAIRM1 as a promising molecular target for bone tissue repair and regeneration. [ABSTRACT FROM AUTHOR]

Background: Non-small cell lung cancer (NSCLC) as the most frequent type of lung cancer is associated with extensive mortality. Researchers have studied the suitability of several molecules as biomarkers for early detection of this cancer. Long non-coding RNAs (lncRNAs) as the main regulators of gene expression have also been assessed in this regard.Methods: In the present study, we compared expression level of Fas-antisense 1 (FAS-AS1), Growth Arrest Specific 5 (GAS5), PVT1, Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1), taurine upregulated gene 1 (TUG1) and TNFα and hnRNPL related immunoregulatory LincRNA (THRIL) in 32 NSCLC samples and their corresponding adjacent non-cancerous tissues (ANCTs).Results: NEAT1 has been significantly over-expressed in NSCLC tissues obtained from male subjects compared with the corresponding ANCTs (Relative expression (REx) = 3.022, P = 0.019) but not in female subjects (P = 0.975). FAS-AS1 was significantly down-regulated in NSCLC tissues obtained from both males and females subjects compared with the corresponding ANCTs (REx = - 4.12 and - 3.14, P = 0.015 and 0.033 respectively). TUG1, GAS5, THRIL and HOTAIRM1 were significantly down-regulated in tumoral tissues obtained from male subjects compared with the corresponding ANCTs.Conclusions: The observed dysregulation of these lncRNAs in NSCLC tissues compared with the corresponding ANCTs warrants future studies to confirm the results of the current study in larger sample sizes to elaborate their role as cancer biomarkers. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) play critical roles in regulation of immunological pathways. Consequently, their expression profile represents new biomarkers for susceptibility and progression of immunological disorders. However, their role in chronic inflammatory diseases such as multiple sclerosis (MS) remained unknown. Here, we assessed the expression of lncRNAs MALAT1 and HOTAIRM1 as well as their target genes in peripheral blood of MS patients to show their possible roles in disease initiation and progression. In this study, 50 patients with relapsing-remitting MS and 50 healthy matched controls were enrolled. Comparative Ct method via TaqMan assay was used to quantify transcript levels of MALAT1, HOTAIRM1, AGO2, CSTF2, CPSF7, and WDR33. Our analysis depicted significant differences in lncRNAs and their target genes expression levels. AGO2 expression was significantly elevated in MS patients (P < 0.001) whereas, CSTF2 expiration was considerably down-regulated (P < 0.042). These findings suggest that AGO2 and CSTF2 can be considered as potential theoretical biomarkers for MS and can be helpful for diagnosis and prognosis of responding patients to interferon. [ABSTRACT FROM AUTHOR]

Abstract Background Long noncoding RNA HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) has been characterized as a critical factor in all-trans retinoic acid (ATRA)-induced differentiation of acute promyelocytic leukemia (APL) cells. However, the essential transcription factor for gene expression of HOTAIRM1 is still unknown. Findings Chromatin immunoprecipitation (ChIP) assays revealed that PU.1 constitutively bound to the regulatory region of HOTAIRM1. Co-expression of PU.1 led to the transactivation of the regulatory region of HOTAIRM1 in a reporter assay. Detailed analysis showed that two PU.1 motifs, which were located around +1100 bp downstream of the transcriptional start site of the HOTAIRM1 promoter, were responsible for the PU.1-dependent transactivation. The induction of HOTAIRM1 by ATRA was dependent on PU.1, and ectopic expression of PU.1 significantly up-regulated HOTAIRM1. Furthermore, low HOTAIRM1 expression was observed in APL cells, which was attributed to the reduced PU.1 expression rather than the repression by PML-RARα via the direct binding. Conclusion PU.1 directly activates the expression of HOTAIRM1 through binding to the regulatory region of HOTAIRM1 during granulocytic differentiation. The reduced PU.1 expression, rather than PML-RARα itself, results in the low expression of HOTAIRM1 in APL cells. Our findings enrich the knowledge on the regulation of lncRNAs and the underlying mechanisms of the abnormal expression of lncRNAs involved in APL.

Abstract: This study is aimed to explore the regulatory effect of lncRNA HOTAIR/miR‐148a/DLGAP1 axis on head and neck tumor (HNT) cell growth, cell mobility, and invasiveness. HOTAIRM1, miR‐148a, and DLGAP1 level in HNT tissues and adjacent normal tissues were measured by qRT‐PCR. Cell Counting Kit‐8 (CCK‐8) and Transwell (migration and invasion) assay were used to survey the influence of HOTAIRM1, miR‐148a, and DLGAP1 on Fadu cells. Nude mouse xenograft was utilized to validate the influence of HOTAIRM1 in vivo. Dual‐luciferase reporter assay confirms the relationship between HOTAIRM1 and miR‐148a, miR‐148a, and DLGAP1. The expression level of HOTAIRM1 was downregulated in human HNT tissues and cells. Overexpression of HOTAIRM1 significantly moderated Fadu cells proliferation, apoptosis, migration, and invasion in vitro and impaired the tumorigenesis in vivo. The expression level of miR‐148a was upregulated in human HNT tissue compared to the adjacent tissues. We identified that miR‐148a was a target of HOTAIRM1 and its expression levels were reduced by HOTAIRM1. Transfection of miR‐148a mimics increased proliferation, migration, and invasion of Fadu cells. DLGAP1 was identified as a novel target of miR‐148a and its expression level was promoted by either HOTAIRM1 overexpression or miR‐148a knockdown. Overexpression of DLGAP1 also facilitated the cell viability and metastasis of Fadu cells. HOTAIRM1 was confirmed as a tumor suppressor via sponging miR‐148a and promote the expression of DLGAP1, which could be regarded as an important target for the prevention and treatment of HNT. [ABSTRACT FROM AUTHOR]

Recent studies have revealed many different long noncoding RNAs (lnc RNA), however, the investigation for their function and clinical value as tumour biomarkers has scarcely begun. Here, we found that expression of HOTAIRM1 was reduced in colorectal cancer ( CRC) tissues compared with matched normal tissues, and plasma HOTAIRM1 levels in CRC patients were less than in controls. The cut-off point was chosen as 0.003 with a sensitivity of 64.00% and a specificity of 76.50% in the validation set. The performance of HOTAIRM1 was highly comparable to carcinoembryonic antigen ( CEA), and better than CA19-9 and CA125. The combined assay of HOTAIRM1 and CEA raised the sensitivity and specificity to 84.00%. HOTAIRM1 knockdown resulted in obvious changes in expression of the cell proliferation related to genes and promoted cell proliferation. HOTAIRM1 plays a role of tumour suppressor in CRC; Down-regulation of HOTAIRM1 can serve as a biomarker for CRC, and combined HOTAIRM1 and CEA assay might provide a promising diagnosis for CRC. [ABSTRACT FROM AUTHOR]