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Background: Homeobox (HOX) A11 antisense RNA (HOXA11-AS) has been identified as a cancer promoting lncRNA and is overexpressed in nephroblastoma. However, how HOXA11-AS is regulated in a hypoxic inflammatory environment has not been studied. Methods: In this study, gene expression and epithelial-mesenchymal transition (EMT) ability were detected in the nephroblastoma cell line WiT49 under conditions of hypoxia and inflammation. Next, HOXA11-AS transcription factors were predicted by datasets and subsequently confirmed by CHIP-QPCR, EMSA, and dual-luciferase reporter assays. Moreover, the regulatory relationships of HOXA11-AS and its transcription factors were further confirmed by rescue experiments. Results: Our results showed that a hypoxic microenvironment promoted HOXA11-AS expression and nephroblastoma progression, induced EMT, and activated the Wnt signaling pathway. Combined hypoxia and inflammation had a more substantial effect on nephroblastoma than either hypoxia or inflammation alone. HIF-1α and C/EBPβ were confirmed to be the transcription factors for HOXA11-AS. Silencing of HIF-1α or C/EBPβ downregulated HOXA11-AS expression and suppressed EMT and the Wnt signaling pathway in nephroblastoma cells exposed to a hypoxic or inflammatory microenvironment. HOXA11-AS overexpression partly reversed the effect of HIF-1α or C/EBPβ knockdown. Conclusion: We demonstrated that hypoxia/inflammation-induced upregulation of HIF-1α and C/EBPβ promoted nephroblastoma EMT by improving HOXA11-AS transcription. HOXA11-AS might be a therapy target for nephroblastoma.

Long non-coding RNA (lncRNA) dysregulation is demonstrated to be associated with disease progression. Mounting studies show that lncRNA promotes or inhibits the development of keloid. We aimed to disclose the role of homebox A11 antisense RNA (HOXA11-AS) in the formation of keloid. Quantitative real-time PCR (qPCR) was adopted for expression analysis of HOXA11-AS, miR-182-5p and zinc finger protein 217 (ZNF217) mRNA, and the expression of ZNF protein and marker proteins was detected by western blot. Cell proliferation, cell migration and cell apoptosis were investigated using CCK-8 assay, wound healing assay and flow cytometry assay, respectively. The potential interplay between miR-182-5p and HOXA11-AS or ZNF217 was verified by dual-luciferase reporter assay, RIP assay and pull-down assay. The role of HOXA11 in vivo was studied by establishing animal models. HOXA11-AS was highly expressed in tissues and fibroblasts of keloid. Deficiency of HOXA11-AS blocked the proliferation and migration of keloid fibroblasts and induced fibroblast apoptosis. HOXA11-AS directly combined to miR-182-5p whose downregulation reversed the effects of HOXA11-AS knockdown. ZNF217 was a target of miR-182-5p, and HOXA11-AS indirectly promoted ZNF217 expression by binding to miR-182-5p. MiR-182-5p enrichment also blocked keloid fibroblast proliferation, survival and migration, while further ZNF217 overexpression abolished these effects. HOXA11-AS knockdown also hindered the growth of keloid in mouse models. High expression of HOXA11-AS promoted the formation and growth of keloid through the upregulation of ZNF217 by targeting miR-182-5p, and the inhibition of HOXA11-AS might be a novel strategy to prevent keloid development. • The expression of HOXA11-AS is enhanced in keloid tissues and fibroblasts. • HOXA11-AS knockdown inhibits the proliferation, survival and motility of keloid fibroblasts. • HOXA11-AS targets miR-182-5p and thus promote the expression of ZNF217. • HOXA11-AS enhances ZNF217 expression by depleting miR-182-5p, leading to keloid fibroblast proliferation and migration, and keloid growth in vivo. [ABSTRACT FROM AUTHOR]

Abstract Background Lung cancer is the most common malignancy in the world and a growing number of researches have focused on its metabolic characteristics. Studies have shown that the long non‐coding RNA (lncRNA) HOXA11‐AS is aberrantly expressed in many tumors. However, the role of HOXA11‐AS in lung adenocarcinoma (LUAD) glycolysis and other energy metabolism pathways has not been characterized. Method The mRNA levels of HOXA11‐AS, microRNA‐148b‐3p (miR‐148b‐3p), and pyruvate kinase M2 (PKM2) were detected using qRT‐PCR. The expression levels of proteins were measured using immunohistochemistry and western blot. The CCK‐8, EdU, and colony formation assays were used to assess proliferation. Glycolytic changes were assessed by measuring lactate production, ATP production, and 18F‐FDG uptake. Bioinformatics analysis and dual‐luciferase reporter assays were used to characterize the relationship between HOXA11‐AS, miR‐148b‐3p, and PKM2. Proliferation and glycolytic changes were analyzed in xenograft tumor experiments using Micro‐PET imaging after downregulation of HOXA11‐AS in vivo. Results The expression of HOXA11‐AS was markedly increased in LUAD, and was strongly associated with a poor prognosis. In addition, HOXA11‐AS promoted proliferation and glycolysis in LUAD, and miR‐148b‐3p inhibited proliferation and glycolysis in LUAD. Mechanistically, HOXA11‐AS positively regulated PKM2 expression by binding to miR‐148b‐3p, thereby promoting LUAD proliferation and glycolysis. In addition, HOXA11‐AS inhibited LUAD xenograft growth and glycolysis via upregulation of miR‐148b‐3p expression and downregulation of PKM2 expression in vivo. Conclusions These results showed that HOXA11‐AS enhanced LUAD proliferation and glycolysis via the miR‐148b‐3p/PKM2 axis. The findings in this paper expanded our understanding of the molecular mechanisms of LUAD tumorigenesis and glycolysis and showed that HOXA11‐AS could be useful as a diagnostic and prognostic marker for LUAD. 18F‐FDG PET/CT can be used to visually evaluate the therapeutic effect of targeting HOXA11‐AS.

Abstract Background Emerging evidence manifests that cyclin‐dependent kinase 6 (CDK6) plays an essential part in the initiation and progression of several types of human cancer, and its descending expression is correlated with an adverse prognosis. However, the precise role of CDK6 in Pancreatic cancer (PC) remains obscure. Aims To identify the potential ceRNA regulatory axis of CDK6 in PC and explore its relationship with immune cells and immune checkpoints. Materials & Methods Using The Cancer Genome Atlas TCGA and GTEx data analyze the expression and survival of CDK6 in patients in pan‐cancer, and cellular experiments were performed to verify the effect of CDK6 on cell function. Using GEPIA and STARBASE databases to analyze prognosis, expression and survival, and identify non coding RNA (ncRNA) that mediates CDK6 overexpression. The TIMER 2.0 database was used for immune correlation analysis. Results We revealed CDK6 might be an oncogene in PC, and the HOXA11‐AS /NR2F1‐AS1‐ miR‐454‐3p axis was identified as the possible upstream ncRNA‐associated pathway of CDK6 in PC. In addition, CDK6 show significant association with three immune checkpoints (PD‐L1, PD‐L2, and HAVCR2), the infiltration level of immune cells, and immunity biomarkers. Discussion We discussed some applications of CDK6 in breast cancer, melanoma, and hemorrhagic malignancies. The role of miR‐15a‐5p, HOXA11‐AS and NR2F1‐AS1 in tumor development was also discussed based on existing studies. The potential mechanism of CDK6 affecting immune cells in pancreatic cancer was discussed. Conclusions Overall, these results established that nc‐RNA‐mediated high expression of CDK6 is associated with patient outcomes and immune invasion in pancreatic cancer.

Background: Emerging evidence manifests that cyclin‐dependent kinase 6 (CDK6) plays an essential part in the initiation and progression of several types of human cancer, and its descending expression is correlated with an adverse prognosis. However, the precise role of CDK6 in Pancreatic cancer (PC) remains obscure. Aims: To identify the potential ceRNA regulatory axis of CDK6 in PC and explore its relationship with immune cells and immune checkpoints. Materials & Methods: Using The Cancer Genome Atlas TCGA and GTEx data analyze the expression and survival of CDK6 in patients in pan‐cancer, and cellular experiments were performed to verify the effect of CDK6 on cell function. Using GEPIA and STARBASE databases to analyze prognosis, expression and survival, and identify non coding RNA (ncRNA) that mediates CDK6 overexpression. The TIMER 2.0 database was used for immune correlation analysis. Results: We revealed CDK6 might be an oncogene in PC, and the HOXA11‐AS /NR2F1‐AS1‐ miR‐454‐3p axis was identified as the possible upstream ncRNA‐associated pathway of CDK6 in PC. In addition, CDK6 show significant association with three immune checkpoints (PD‐L1, PD‐L2, and HAVCR2), the infiltration level of immune cells, and immunity biomarkers. Discussion: We discussed some applications of CDK6 in breast cancer, melanoma, and hemorrhagic malignancies. The role of miR‐15a‐5p, HOXA11‐AS and NR2F1‐AS1 in tumor development was also discussed based on existing studies. The potential mechanism of CDK6 affecting immune cells in pancreatic cancer was discussed. Conclusions: Overall, these results established that nc‐RNA‐mediated high expression of CDK6 is associated with patient outcomes and immune invasion in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the most common malignancy in the world and a growing number of researches have focused on its metabolic characteristics. Studies have shown that the long non‐coding RNA (lncRNA) HOXA11‐AS is aberrantly expressed in many tumors. However, the role of HOXA11‐AS in lung adenocarcinoma (LUAD) glycolysis and other energy metabolism pathways has not been characterized. Method: The mRNA levels of HOXA11‐AS, microRNA‐148b‐3p (miR‐148b‐3p), and pyruvate kinase M2 (PKM2) were detected using qRT‐PCR. The expression levels of proteins were measured using immunohistochemistry and western blot. The CCK‐8, EdU, and colony formation assays were used to assess proliferation. Glycolytic changes were assessed by measuring lactate production, ATP production, and 18F‐FDG uptake. Bioinformatics analysis and dual‐luciferase reporter assays were used to characterize the relationship between HOXA11‐AS, miR‐148b‐3p, and PKM2. Proliferation and glycolytic changes were analyzed in xenograft tumor experiments using Micro‐PET imaging after downregulation of HOXA11‐AS in vivo. Results: The expression of HOXA11‐AS was markedly increased in LUAD, and was strongly associated with a poor prognosis. In addition, HOXA11‐AS promoted proliferation and glycolysis in LUAD, and miR‐148b‐3p inhibited proliferation and glycolysis in LUAD. Mechanistically, HOXA11‐AS positively regulated PKM2 expression by binding to miR‐148b‐3p, thereby promoting LUAD proliferation and glycolysis. In addition, HOXA11‐AS inhibited LUAD xenograft growth and glycolysis via upregulation of miR‐148b‐3p expression and downregulation of PKM2 expression in vivo. Conclusions: These results showed that HOXA11‐AS enhanced LUAD proliferation and glycolysis via the miR‐148b‐3p/PKM2 axis. The findings in this paper expanded our understanding of the molecular mechanisms of LUAD tumorigenesis and glycolysis and showed that HOXA11‐AS could be useful as a diagnostic and prognostic marker for LUAD. 18F‐FDG PET/CT can be used to visually evaluate the therapeutic effect of targeting HOXA11‐AS. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis (OP) is one of the most common bone diseases, resulting in increased mortality, persistent disability, and reduced quality of life. It is characterized by bone loss and low bone quality. Objective: The objective of this study was to detect possible effects of HOXA11-AS on the progression of Osteoporosis (OP) and investigate the potential downstream targets. Results: We found HOXA11-AS was low expression in BMSCs of OVX-induced rats. HOXA11-AS promoted osteoblastic differentiation and the expression of osteoblastic genes in BMSCs. Mechanically, we found HOXA11-AS negatively regulated the expression of miR-208a-3p, and miR-208a-3p could further target ETS proto-oncogene 1 (ETS1) in BMSCs. We further demonstrated HOXA11-AS promoted osteogenic differentiation of BMSCs through ETS1. Conclusion: We therefore thought HOXA11-AS could serve as a promising target for the treatment of OP. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) participate in many pathophysiological processes after traumatic brain injury by mediating neuroinflammation and apoptosis. Homeobox A11 antisense RNA (HOXA11-AS) is a member of the lncRNA family that has been reported to participate in many inflammatory reactions; however, its role in traumatic brain injury remains unclear. In this study, we established rat models of traumatic brain injury using a weight-drop hitting device and injected LV-HOXA11-AS into the right lateral ventricle 2 weeks before modeling. The results revealed that overexpression of HOXA11-AS aggravated neurological deficits in traumatic brain injury rats, increased brain edema and apoptosis, promoted the secretion of proinflammatory factors interleukin-1β, interleukin-6, and tumor necrosis factor α, and promoted the activation of astrocytes and microglia. Microglia were treated with 100 ng/mL lipopolysaccharide for 24 hours to establish in vitro cell models, and then transfected with pcDNA-HOXA11-AS, miR-124-3p mimic, or sh-MDK. The results revealed that HOXA11-AS inhibited miR-124-3p expression and boosted MDK expression and TLR4-nuclear factor-κB pathway activation. Furthermore, lipopolysaccharide enhanced potent microglia-induced inflammatory responses in astrocytes. Forced overexpression of miR-124-3p or downregulating MDK repressed microglial activation and the inflammatory response of astrocytes. However, the miR-124-3p-mediated anti-inflammatory effects were reversed by HOXA11-AS. These findings suggest that HOXA11-AS can aggravate neuroinflammation after traumatic brain injury by modulating the miR-124-3p-MDK axis. This study was approved by the Animal Protection and Use Committee of Southwest Medical University (approval No. SMU-2019-042) on February 4, 2019.

Abstract Background miR-124-3p can inhibit integrin β3 (ITGB3) expression to suppress the migration and invasion of gastric cancer (GC), and in the process lncRNA HOXA11-AS may act as a molecular sponge. Methods Luciferase reporter assay was conducted to verify the binding of miR-124-3p and HOXA11-AS. RT-PCR and western blot were performed to detect the expression of HOXA11-AS, miR-124-3p and ITGB3 in GC tissues and cells. Gene silence and overexpression experiments as well as cell migration and invasion assays on GC cell lines were performed to determine the regulation of molecular pathways, HOXA11-AS/miR-124-3p/ITGB3. Furthermore, the role of HOXA11-AS in GC was confirmed in mice models. Results We found HOXA11-AS is up-regulated in GC tissues and can bind with miR-124-3p. Through overexpression/knockdown experiments and function tests in vitro, we demonstrated HOXA11-AS can promote ITGB3 expression by sponging miR-124-3p, consequently enhance the proliferation, migration, and invasion of GC cells. Meanwhile, we validated that HOXA11-AS promotes migration and invasion of GC cells via down-regulating miR-124-3p and up-regulating ITGB3 in vivo. Conclusions We demonstrated that lncRNA HOXA11-AS can increase ITGB3 expression to promote the migration and invasion of gastric cancer by sponging miR-124-3p. Our results suggested that HOXA11-AS may reasonably serve as a promising diagnostic biomarker and a potential therapeutic target of GC.

Long non-coding RNAs (lncRNAs) play critical roles in human cancers. HOXA11 anti-sense RNA (HOXA11-AS) is an lncRNA belonging to the homeobox (HOX) gene cluster that promotes liver metastasis in human colon cancer. However, its role and mechanism of action in human oral squamous cell carcinoma (OSCC) are unclear. In this study, we investigated HOXA11-AS expression and function in human OSCC tissues and cell lines, as well as a mouse model of OSCC. Our analyses showed that HOXA11-AS expression in human OSCC cases correlates with lymph node metastasis, nicotinamide adenine dinucleotide (NAD)(P)H: quinone oxidoreductase 1 (NQO1) upregulation, and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) downregulation. Using the human OSCC cell lines HSC3 and HSC4, we demonstrate that HOXA11-AS promotes NQO1 expression by sponging microRNA-494. In contrast, HOXA11-AS recruits zeste homolog 2 (EZH2) to the NQO2 promoter to suppress its expression via the trimethylation of H3K27. The upregulation of NQO1 enzymatic activity by HOXA11-AS results in the consumption of flavin adenine dinucleotide (FAD), which reduces FAD-requiring glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity and suppresses glycolysis. However, our analyses show that lactic acid fermentation levels are preserved by glutaminolysis due to increased malic enzyme-1 expression, promoting enhanced proliferation, invasion, survival, and drug resistance. In contrast, suppression of NQO2 expression reduces the consumption of NRH via NQO2 enzymatic activity and increases NAD levels, which promotes enhanced stemness and metastatic potential. In mouse tumor models, knockdown of HOXA11-AS markedly suppressed tumor growth and lung metastasis. From these findings, targeting HOXA11-AS may strongly suppress high-grade OSCC by regulating both NQO1 and NQO2. [ABSTRACT FROM AUTHOR]

Hypopharyngeal squamous cell carcinoma (HSCC) is one of the high mortality cancers with a poor prognosis, which is driving the development of new chemotherapeutic agents. We identified the anticancer effects of a natural compound, solamargine (SM), on FaDU cells and explored its mechanism in terms of non-coding RNA. It was observed that SM inhibited the proliferation of FaDU cells with an IC50 of 5.17 µM. High-throughput sequencing data revealed that lncRNA HOXA11-AS was significantly downregulated in cells co-incubated with SM. Further assays demonstrated that SM-induced downregulation of lncRNA HOXA11-AS showed important implications for apoptosis. Given the properties of HOXA11-AS as a miR-155 sponge, we further confirmed that SM upregulated the expression of miR-155 in FaDU cells. C-Myc is a transcription factor that regulates cell differentiation and apoptosis, whose mRNA is considered to be targeted by miR-155. We showed that c-Myc expression was downregulated by SM and accompanied by increased apoptosis, which was consistent with the findings of transcriptome sequencing. Furthermore, SM administration suppressed xenograft tumor growth in a xenograft mouse model in vivo. In the light of the aforementioned findings, our results suggested that SM downregulated the expression of HOXA11-AS, which in turn induces apoptosis by downregulating c-Myc in FaDU, providing evidence for the anticancer effect of SM on HSCC and uncovering the effect of SM on non-coding RNAs as, at least partly, a mechanism of action. [ABSTRACT FROM AUTHOR]

Keloids are pathologic wound healing conditions caused by fibroblast hyperproliferation and excess collagen deposition following skin injury or irritation, which significantly impact patients by causing psychosocial and functional distress. Extracellular matrix (ECM) deposition and human fibroblast proliferation represents the main pathophysiology of keloid. Long non-coding RNAs (LncRNAs) play important roles in many biological and pathological processes, including development, differentiation and carcinogenesis. Recently, accumulating evidences have demonstrated that deregulated lncRNAs contribute to keloids formation. The present review summarizes the researches of deregulated lncRNAs in keloid. Exploring lncRNA-based methods hold promise as new effective therapies against keloid.

Abnormal expression of long non-coding RNA (lncRNA) has been proved to be related to the formation of keloid. Homeobox A11 antisense (HOXA11-AS) has been found to be a significantly upregulated lncRNA in keloid tissues. To explore the mechanism of HOXA11-AS regulates keloid formation. Primary fibroblasts were isolated from keloid tissues and normal skin tissues. The expression of HOXA11-AS, microRNA (miR)−188–5p and vascular endothelial growth factor A (VEGFA) was determined using quantitative real-time PCR (qRT-PCR). Cell counting kit 8 (CCK8) assay, EdU staining, flow cytometry and wound healing assay were performed to assess the proliferation, cell cycle process, apoptosis and migration of keloid fibroblasts. Importantly, some marker protein levels and VEGFA protein level were examined by western blot (WB) analysis. The interaction between miR-188–5p and HOXA11-AS or VEGFA was confirmed using dual-luciferase reporter assay, RNA pull-down assay and RIP assay. Animal experiments were performed to further confirm the role of HOXA11-AS in keloid growth. HOXA11-AS was markedly upregulated in keloid tissues and fibroblasts. Knockdown of HOXA11-AS repressed the proliferation, cell cycle process, migration and promoted the apoptosis of keloid fibroblasts. Further analysis suggested that HOXA11-AS could sponge miR-188–5p to positively regulate VEGFA. The inhibition of HOXA11-AS silencing on the biological functions of keloid fibroblasts could be reversed by miR-188–5p inhibitor. In addition, VEGFA overexpression also abolished the suppressive effect of miR-188–5p on the biological functions of keloid fibroblasts. Interferences of HOXA11-AS suppressed keloid growth in vivo. HOXA11-AS might regulate the miR-188–5p/VEGFA axis to promote keloid formation. • Downregulation of HOXA11-AS inhibits keloid fibroblast proliferation, cell cycle process, migration and enhances apoptosis. • HOXA11-AS acts as a ceRNA for miR-188–5p. • MiR-188–5p interacts with VEGFA. [ABSTRACT FROM AUTHOR]

Background: Long non‐coding RNAs (lncRNAs) play vital roles in tumorigenesis. Here, we explored how lncRNA HOXA11‐AS functions in the progression of breast cancer (BC). Methods: HOXA11‐AS and miR‐125a‐5p levels were measured by a quantitative real‐time polymerase chain reaction, whereas western blotting determined TMPRSS4 levels in BC tumor tissues, adjacent normal tissues and BC cell lines. The roles of HOXA11‐AS, miR‐125a‐5p and TMPRSS4 in BC proliferation were investigated using cell counting kit‐8, colony formation and flow cytometry assays, whereas scratch and transwell assays were used to measure metastasis. RNA pull‐down assays and dual‐luciferase assays assessed direct interactions between HOXA11‐AS and miR‐125a‐5p. The effects of HOXA11‐AS in vivo were investigated in a BC xenograft model. Results: HOXA11‐AS was upregulated in tumor tissues of 56 BC patients compared to adjacent non‐tumor tissues, with high levels being associated with worse overall survival. Silencing of HOXA11‐AS inhibited the proliferation and metastasis of BC cells, leading to cell cycle arrest in G0/G1 and induction of apoptosis. We identified miR‐125a‐5p as a target of HOXA11‐AS, with miR‐125a‐5p inhibitors partially restoring the reduction of cell proliferation and metastasis induced by HOXA11‐AS silencing. We also determined that miR‐125a‐5p targeted TMPRSS4 mRNA, with HOXA11‐AS knockdown and miR‐125a‐5p mimics suppressing TMPRSS4. Overexpression of TMPRSS4 partially compensated for the reduction of cell proliferation and metastasis induced by HOXA11‐AS silencing. Finally, we confirmed the mechanism of HOXA11‐AS in the regulation of tumorigenesis in the mouse model. Conclusions: HOXA11‐AS regulates the tumorigenic ability of BC via the miR‐125a‐5p/TMPRSS4 axis. This provides insights for regulatory mechanisms involved in BC progression, and may enable new treatment strategies in the clinical setting. [ABSTRACT FROM AUTHOR]

Cao K, Fang Y, Wang H, Jiang Z, Guo L, Hu Y. Cancer Manag Res. 2019;11:4505–4518. The authors have advised due to an error at the time of figure assembly, Figure 3B on page 4512 is incorrect. The correct Figure 3 is shown in Download Article. The authors apologize for this error and advise it does not affect the results of the paper. Read the original article

Yongfei Xu,1,2 Jianwen Zhang,1 Qiangqiang Zhang,3 Hangxing Xu,4 Linbo Liu1 1Department of Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan, People’s Republic of China; 2Department of Plastic Surgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang City, Henan, People’s Republic of China; 3Burn Plastic Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang City, Henan, People’s Republic of China; 4Department of Surgery, Luoyang Central Tunnel Hospital, Luoyang City, Henan, People’s Republic of ChinaCorrespondence: Linbo LiuDepartment of Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Jinshui District, Zhengzhou, 450000, Henan, People’s Republic of ChinaTel +86-13937196215Email pingtengfut8s@126.comBackground: Long non-coding RNA homeobox A11 antisense RNA (HOXA11-AS) was showed to participate in the progression of different kinds of tumors, but the specific role of HOXA11-AS in cutaneous melanoma is not entirely unambiguous.Methods: The levels of HOXA11-AS, microRNA-152-3p (miR-152-3p) and integrin alpha9 (ITGA9) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was detected via 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT), and apoptosis was measured by flow cytometry. The assessment of cell metastasis was performed by transwell migration and invasion assays. The protein levels were detected through Western blot. Dual-luciferase reporter assay was utilized to explore the target relationship among HOXA11-AS, miR-152-3p and ITGA9. The effect of HOXA11-AS on melanoma in vivo was investigated via xenograft experiment.Results: HOXA11-AS and ITGA9 were up-regulated while miR-152-3p was down-regulated in melanoma. Knockdown of HOXA11-AS refrained cell proliferation, metastasis and epithelial–mesenchymal transition (EMT) but induced apoptosis in melanoma cells. HOXA11-AS targeted miR-152-3p and overexpression of HOXA11-AS mitigated the miR-152-3p-induced effects on melanoma cellular behaviors. ITGA9 was a target of miR-152-3p and miR-152-3p inhibitor relieved the repression on proliferation, metastasis and EMT while elevation on apoptosis caused by si-ITGA9 via elevating ITGA9. HOXA11-AS knockdown restrained ITGA9 expression via up-regulating miR-152-3p. Suppression of HOXA11-AS inhibited melanoma progression in part through increasing miR-152-3p and decreasing ITGA9 expression in vivo.Conclusion: HOXA11-AS modulated proliferation, apoptosis, metastasis and EMT in melanoma cells by regulating miR-152-3p/ITGA9 axis in part. HOXA11-AS could promote melanoma development and be used as a promising biomarker in the diagnosis and treatment for cutaneous melanoma.Keywords: melanoma, HOXA11-AS, miR-152-3p, ITGA9

Background: Expression of the long noncoding RNA (lncRNA) HOXA11-AS significantly increased in keloids by unclarified molecular regulation mechanisms. Methods: Using successfully primary cultured keloid-derived fibroblasts from central region of chronic keloid tissues (sample 0), small interfering RNAs were designed and transfected into two keloid fibroblast samples (samples 1 and 2) to knockdown HOXA11-AS. One nonspecific transfection control (sample 3) and one blank control (sample 4) were used to remove nonspecific overlap from the studied group. The lncRNAs, messenger RNAs (mRNAs), and microRNAs (miRNAs) of five samples were sequenced to identify differentially expressed (DE) profiles in HOXA11-AS-knockdown keloid fibroblasts in samples 1 and 2 (by intersection), which facilitated removal of overlap with the nonspecific controls (samples 3 and 4, by union). Using stepwise bioinformatic analysis, a HOXA11-AS-interacted competing endogenous network (ceRNA) was screened based on three DE profiles. Results: Keloid fibroblasts with or without HOXA11-AS as well as with or without nonspecific interferences were successfully constructed respectively. A total of 1,396 mRNAs and 39 lncRNAs were significantly changed in keloid fibroblast with HOXA11-AS knockdown. Simultaneously, 1,626 mRNAs and 99 lncRNAs were significantly changed in keloid fibroblast with nonspecific interference. With removal of nonspecific overlap, a lncRNA–mRNA interactive network characterized by close natural/intronic antisense relationship was initially constructed in keloid fibroblast with HOXA11-AS knockdown. Based on this network, a lncRNA–mRNA–protein interaction network was extended by integration of the human protein–protein interaction network. Significant functional genes were screened using PageRank algorithm in the extended network. Three genes, including SNED1, NIPAL3, and VTN, were validated by real-time PCR in HOXA11-AS-knockdown keloid fibroblasts. Only NIPAL3 was predicted to be a target gene for HOXA11-AS via three competing endogenous miRNAs (hsa-miRNA-19a-3p, hsa-miR-141-3p, and hsa-miR-140-5p). Conclusion: An interactive network of HOXA11-AS–three miRNAs–NIPAL3 was predicted in keloid fibroblasts by integrative bioinformatic analysis and in vitro validation. [ABSTRACT FROM AUTHOR]

Objective: This study investigates the relationship between the HOXA11-AS/let-7c-5p/IGF2BP1 regulatory axis and lung adenocarcinoma. Methods: The expression levels of HOXA11-AS, let-7c-5p, and IGF2BP1 were evaluated in LUAD tissue and cell lines. Subcellular fractionation detection assay was adopted to verify the HOXA11-AS distribution in LUAD cells. The interaction relationship between let-7c-5p and HOXA11-AS or IGF2BP1 was validated by dual-luciferase reporter detection. In RNA binding protein immunoprecipitation assay, the binding relationship between HOXA11-AS and let-7c-5p was identified. The cell viability of transfected cells was tested by the Cell Counting Kit-8 assay. The mouse xenograft model was used to identify the effect of HOXA11-AS on tumor growth in vivo. Results: Upregulation of lncRNA HOXA11-AS was found in LUAD, and suppression of HOXA11-AS could suppress the proliferative ability of LUAD cells. The let-7c-5p was expressed to be downregulated, which played an inhibitory role in LUAD cell proliferation. Let-7c-5p was negatively regulated by HOXA11-AS. HOXA11-AS promoted LUAD cell proliferation, while let-7c-5p had an inverse effect. Besides, IGF2BP1, regulated by let-7c-5p, had a positive relation with HOXA11-AS, while overexpression of IGF2BP1 could suppress the inhibition of silencing HOXA11-AS on LUAD cell proliferation. Experiments on mice confirmed that HOXA11-AS facilitated LUAD cell growth in vivo through regulating the let-7c-5p/IGF2BP1 axis. Conclusion: HOXA11-AS promoted LUAD cell proliferation by targeting let-7c-5p/IGF2BP1, which could be potential molecular targets for LUAD. [ABSTRACT FROM AUTHOR]

Objective: This study investigates the relationship between the HOXA11-AS/let-7c-5p/IGF2BP1 regulatory axis and lung adenocarcinoma.Methods: The expression levels of HOXA11-AS, let-7c-5p, and IGF2BP1 were evaluated in LUAD tissue and cell lines. Subcellular fractionation detection assay was adopted to verify the HOXA11-AS distribution in LUAD cells. The interaction relationship between let-7c-5p and HOXA11-AS or IGF2BP1 was validated by dual-luciferase reporter detection. In RNA binding protein immunoprecipitation assay, the binding relationship between HOXA11-AS and let-7c-5p was identified. The cell viability of transfected cells was tested by the Cell Counting Kit-8 assay. The mouse xenograft model was used to identify the effect of HOXA11-AS on tumor growth in vivo.Results: Upregulation of lncRNA HOXA11-AS was found in LUAD, and suppression of HOXA11-AS could suppress the proliferative ability of LUAD cells. The let-7c-5p was expressed to be downregulated, which played an inhibitory role in LUAD cell proliferation. Let-7c-5p was negatively regulated by HOXA11-AS. HOXA11-AS promoted LUAD cell proliferation, while let-7c-5p had an inverse effect. Besides, IGF2BP1, regulated by let-7c-5p, had a positive relation with HOXA11-AS, while overexpression of IGF2BP1 could suppress the inhibition of silencing HOXA11-AS on LUAD cell proliferation. Experiments on mice confirmed that HOXA11-AS facilitated LUAD cell growth in vivo through regulating the let-7c-5p/IGF2BP1 axis.Conclusion: HOXA11-AS promoted LUAD cell proliferation by targeting let-7c-5p/IGF2BP1, which could be potential molecular targets for LUAD.

Background: Expression of the long noncoding RNA (lncRNA) HOXA11-AS significantly increased in keloids by unclarified molecular regulation mechanisms.Methods: Using successfully primary cultured keloid-derived fibroblasts from central region of chronic keloid tissues (sample 0), small interfering RNAs were designed and transfected into two keloid fibroblast samples (samples 1 and 2) to knockdown HOXA11-AS. One nonspecific transfection control (sample 3) and one blank control (sample 4) were used to remove nonspecific overlap from the studied group. The lncRNAs, messenger RNAs (mRNAs), and microRNAs (miRNAs) of five samples were sequenced to identify differentially expressed (DE) profiles in HOXA11-AS-knockdown keloid fibroblasts in samples 1 and 2 (by intersection), which facilitated removal of overlap with the nonspecific controls (samples 3 and 4, by union). Using stepwise bioinformatic analysis, a HOXA11-AS-interacted competing endogenous network (ceRNA) was screened based on three DE profiles.Results: Keloid fibroblasts with or without HOXA11-AS as well as with or without nonspecific interferences were successfully constructed respectively. A total of 1,396 mRNAs and 39 lncRNAs were significantly changed in keloid fibroblast with HOXA11-AS knockdown. Simultaneously, 1,626 mRNAs and 99 lncRNAs were significantly changed in keloid fibroblast with nonspecific interference. With removal of nonspecific overlap, a lncRNA–mRNA interactive network characterized by close natural/intronic antisense relationship was initially constructed in keloid fibroblast with HOXA11-AS knockdown. Based on this network, a lncRNA–mRNA–protein interaction network was extended by integration of the human protein–protein interaction network. Significant functional genes were screened using PageRank algorithm in the extended network. Three genes, including SNED1, NIPAL3, and VTN, were validated by real-time PCR in HOXA11-AS-knockdown keloid fibroblasts. Only NIPAL3 was predicted to be a target gene for HOXA11-AS via three competing endogenous miRNAs (hsa-miRNA-19a-3p, hsa-miR-141-3p, and hsa-miR-140-5p).Conclusion: An interactive network of HOXA11-AS–three miRNAs–NIPAL3 was predicted in keloid fibroblasts by integrative bioinformatic analysis and in vitro validation.

Background: miR-124-3p can inhibit integrin β3 (ITGB3) expression to suppress the migration and invasion of gastric cancer (GC), and in the process lncRNA HOXA11-AS may act as a molecular sponge. Methods: Luciferase reporter assay was conducted to verify the binding of miR-124-3p and HOXA11-AS. RT-PCR and western blot were performed to detect the expression of HOXA11-AS, miR-124-3p and ITGB3 in GC tissues and cells. Gene silence and overexpression experiments as well as cell migration and invasion assays on GC cell lines were performed to determine the regulation of molecular pathways, HOXA11-AS/miR-124-3p/ITGB3. Furthermore, the role of HOXA11-AS in GC was confirmed in mice models. Results: We found HOXA11-AS is up-regulated in GC tissues and can bind with miR-124-3p. Through overexpression/knockdown experiments and function tests in vitro, we demonstrated HOXA11-AS can promote ITGB3 expression by sponging miR-124-3p, consequently enhance the proliferation, migration, and invasion of GC cells. Meanwhile, we validated that HOXA11-AS promotes migration and invasion of GC cells via down-regulating miR-124-3p and up-regulating ITGB3 in vivo. Conclusions: We demonstrated that lncRNA HOXA11-AS can increase ITGB3 expression to promote the migration and invasion of gastric cancer by sponging miR-124-3p. Our results suggested that HOXA11-AS may reasonably serve as a promising diagnostic biomarker and a potential therapeutic target of GC. [ABSTRACT FROM AUTHOR]

Objective To investigate the expression and clinical significance of long-chain non-coding RNA(lncRNA) HOXA11-AS in hepatocellular carcinoma. Methods We included 106 patients with primary liver cancer. qRT-PCR was used to detect the expression of lncRNA HOXA11-AS in liver cancer tissues and adjacent normal tissues, and we analyzed its correlation with clinicopathological features and prognosis of the patients. Results The expression of lncRNA HOXA11-AS in liver cancer tissues was significantly higher than that in adjacent normal tissues (2.97±0.81 vs. 0.83±0.22, P < 0.05); it was significantly different in the liver cancer tissues with different AJCC staging and lymph node metastasis (P < 0.05). The 3-year survival rate of the high lncRNA HOXA11-AS expression group was significantly lower than that of the low expression group (22.22% vs. 53.33%, P < 0.05). High lncRNA HOXA11-AS expression and AJCC staging were independent risk factors for the prognosis of primary liver cancer patients (P < 0.05). Conclusion The expression of lncRNA HOXA11-AS in liver cancer tissues is upregulated. It may be involved in the occurrence and development of liver cancer and may become a new indicator for the prognosis evaluation of liver cancer patients.

Jiapeng Xu,1,* Yu Zhang,1,* Qing You,1 Hongbing Fu,1 Xiaokai Zhao,2 Kai Lu,2 Ronglin Yan,1 Dejun Yang1 1Department of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, People’s Republic of China; 2Shanghai Yunying Medical Technology Co.Ltd, Shanghai 201600, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ronglin Yan; Dejun YangDepartment of Gastrointestinal Surgery, Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Huangpu District, Shanghai 200003, People’s Republic of ChinaEmail yanronglin@smmu.edu.cn; yangdejun@smmu.edu.cnIntroduction: It is worldwide accepted that lncRNA PTCSC3 is a tumor suppressor in glioma and thyroid cancer, whereas its role in the recurrence of gastric cancer is unknown.Patients and Methods: We recruited 80 GC patients (46 males and 34 females, 44 to 68 years, 56.3± 6.7 years) in our study. Two human GC cell lines AGS and SNU-1 were transfected with PTCSC3 and HOXA11-AS expression vectors. Then, qPCR was used to detect the level of relative mRNA. Both invasion and migration assays were performed to detect the effect of the lncRNA on gastric cancer cell motility.Results: In the present study, we showed that PTCSC3 was downregulated in plasma of gastric cancer patients than in plasma of healthy controls. Follow-up study indicated that PTCSC3 was further downregulated in patients with distant-recurrence but not in patients with local recurrence only or non-recurrence. LncRNA HOXA11-AS was upregulated in plasma of gastric cancer cells than in plasma of healthy controls and was inversely correlated with PTCSC3 in plasma of gastric cancer patients. PTCSC3 overexpression mediated the downregulation of HOXA11-AS in gastric cancer cells, while HOXA11-AS overexpression failed to significantly affect PTCSC3. PTCSC3 overexpression led to inhibited, while HOXA11-AS overexpression led to promoted migration and invasion of gastric cancer cells. In addition, HOXA11-AS overexpression reduced the effects of PTCSC3 overexpression.Discussion: Therefore, lncRNA PTCSC3 alleviates in the postoperative distant recurrence of gastric cancer possible by suppression of HOXA11-AS.Keywords: PTCSC3, gastric cancer, distant recurrence, HOXA11-AS

Yue Bai,1 Lili Lang,2 Wentao Zhao,1 Rong Niu1 1Department One of Thoracic Surgery, Gansu Provincial Cancer Hospital, Gansu, People’s Republic of China; 2Department of Radiology, Gansu Provincial Cancer Hospital, Gansu, People’s Republic of ChinaCorrespondence: Rong NiuDepartment One of Thoracic Surgery, Gansu Provincial Cancer Hospital, No.2, Little West Lake, East Street, Qilihe District, Lanzhou City, Gansu Province, People’s Republic of ChinaTel +86-13893604704Email rhjren12@sina.comObjective: Our present study aimed to further investigate the molecular basis of long non-coding RNA homeobox A11 antisense (HOXA11-AS) in the tumorigenesis of non-small cell lung cancer (NSCLC).Methods: HOXA11-AS, microRNA-148a-3p (miR-148a-3p), and DNA methyltransferase 1 (DNMT1) mRNA levels were measured by RT-qPCR assay. DNMT1 protein level was determined by Western blot assay. Cell proliferative capacity and apoptotic rate were determined by CCK-8 assay and flow cytometry analysis, respectively. The relationships of HOXA11-AS, miR-148a-3p, and DNMT1 were tested through bioinformatics analysis, luciferase assay, and RNA pull down assay. Mouse xenograft models of NSCLC were established to examine the biological function of HOXA11-AS in vivo.Results: HOXA11-AS expression was notably upregulated and miR-148a-3p expression was conspicuously downregulated in NSCLC tissues and cells. HOXA11-AS knockdown curbed NSCLC cell proliferation and promoted cell apoptosis through directly increasing miR-148a-3p expression. Moreover, miR-148a-3p overexpression suppressed NSCLC cell proliferation and induced cell apoptosis. HOXA11-AS functioned as a competing endogenous RNA (ceRNA) of miR-148a-3p to increase DNMT1 expression in NSCLC cells. And, DNMT1 upregulation weakened the influence of HOXA11-AS1 loss on NSCLC cell proliferation and apoptosis. Additionally, HOXA11-AS knockdown suppressed NSCLC xenograft growth by upregulating miR-148a-3p and downregulating DNMT1 in vivo.Conclusion: HOXA11-AS facilitated NSCLC tumorigenesis through miR-148a-3p/DNMT1 axis in vitro and in vivo, deepening our understanding of the molecular basis of HOXA11-AS in the development of NSCLC.Keywords: non-small cell lung cancer, tumorigenesis, HOXA11-AS, miR-148a-3p, DNMT1

HOXA11, which is a member of the homeobox (HOX) gene family, and its natural antisense transcript (NAT) HOXA11-AS have been reported to be closely related to the development of lung cancer. We aimed to investigate their specific roles in cisplatin (DDP) resistance in lung adenocarcinoma (LUAD). First, we found that HOXA11 is hypermethylated and significantly downregulated in a DDP-resistant A549 cell line (A549/DDP) and LUAD tissues, while the HOXA11-AS expression level is elevated. Although HOXA11 and HOXA11-AS mRNA overlap in the 5ʹ-untranslated region (5ʹ UTR) and share two CpG islands, DNA methylation only regulates the expression of HOXA11. Then, we found that HOXA11 and HOXA11-AS have an inverse interaction by transfecting their siRNAs and overexpression vectors into A549 and A549/DDP cells. A dual-luciferase reporter assay further confirmed that the overlapping 5ʹUTR is essential for the bidirectional regulation between HOXA11 and HOXA11-AS. Functional analysis showed that knockdown of HOXA11 expression in A549 cells induced DDP resistance and activated Akt/β-catenin signaling, while overexpression of HOXA11 in A549/DDP cells increased DDP sensitivity and inhibited Akt/β-catenin signaling. Moreover, HOXA11-AS knockdown in A549 cells increased DDP sensitivity and inhibited Akt/β-catenin signaling, while the overexpression of HOXA11-AS in A549/DDP cells induced DDP resistance and activated Akt/β-catenin signaling. In conclusion, our study demonstrates that the inverse interaction between HOXA11 and HOXA11-AS promotes DDP resistance in LUAD.

Accumulating evidence suggested that many long noncoding RNAs (lncRNAs) were widely involved in the development and progression of non-small cell lung cancer (NSCLC). However, the roles of lncRNA homeobox A11 antisense (HOXA11-AS) and its underlying mechanism in NSCLC remains largely unknown. The expression levels of HOXA11-AS, miR-3619-5p and sal-like protein 4 (SALL4) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot analysis was used to measure the protein levels of hexokinase II (HK2) and SALL4. Cell proliferation, apoptosis, migration and invasion were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry and transwell assay, respectively. The glucose consumption and lactate production were measured using glucose assay kit and lactate assay kit, respectively. The potential binding sites between miR-3619-5p and HOXA11-AS or SALL4 were predicted by online software and verified by luciferase report assay. A xenograft tumor model was established to confirm the function of HOXA11-AS in NSCLC in vivo. HOXA11-AS and SALL4 were upregulated while miR-3619-5p was downregulated in NSCLC tissues and cells. HOXA11-AS knockdown suppressed cell proliferation, migration, invasion, and glycolysis but promoted apoptosis in NSCLC cells. Moreover, miR-3619-5p could directly bind to HOXA11-AS and its inhibition attenuated the inhibitory effect of HOXA11-AS knockdown on progression of NSCLC cells. Furthermore, SALL4 was a direct target of miR-3619-5p and its overexpression reversed the anti-tumor role of miR-3619-5p in NSCLC cells. Besides, HOXA11-AS modulated SALL4 expression via sponging miR-3619-5p. Additionally, silencing HOXA11-AS inhibited tumor growth though upregulating miR-3619-5p and downregulating SALL4. Collectively, HOXA11-AS knockdown inhibited the progression of NSCLC by regulating miR-3619-5p/SALL4 axis, which might offer a novel avenue for interpreting the mechanism of NSCLC development. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Long noncoding RNA (lncRNA) was found to play crucial roles in regulating cancer progression. HOXA11 antisense RNA (HOXA11-AS) was reported to serve an oncogenic lncRNA in cancers but its role in prostate cancer (PCa) remains to be explored. MATERIALS AND METHODS: Expression levels of HOXA11-AS in PCa tissues and cells were analyzed with quantitative Real-Time PCR method. MTT assay, colony formation assay, transwell invasion assay, and flow cytometry assay were conducted to explore the biological roles of HOXA11-AS in PCa. Rescue experiments were conducted to investigate mechanisms of HOXA11-AS in regulating PCa progression. RESULTS: We revealed that HOXA11-AS was upregulated in PCa. Silencing of HOXA11-AS significantly inhibited PCa cell proliferation, colony formation, invasion, and promoted apoptosis in vitro. On the contrary, forcing of HOXA11-AS expression caused opposite effects on cancer cell behaviors. Furthermore, we showed that HOXA11-AS1 serves as a competing endogenous RNA (ceRNA) to regulate Jupiter microtubule associated homolog 1 (JPT1) via sponging microRNA-24-3p (miR-24-3p). Functionally, the overexpression of miR-24-3p or knockdown of JPT1 could partially reverse the effects of HOXA11-AS overexpression on PCa cell behaviors. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) play critical roles in human cancers. HOXA11 anti-sense RNA (HOXA11-AS) is an lncRNA belonging to the homeobox (HOX) gene cluster that promotes liver metastasis in human colon cancer. However, its role and mechanism of action in human oral squamous cell carcinoma (OSCC) are unclear. In this study, we investigated HOXA11-AS expression and function in human OSCC tissues and cell lines, as well as a mouse model of OSCC. Our analyses showed that HOXA11-AS expression in human OSCC cases correlates with lymph node metastasis, nicotinamide adenine dinucleotide (NAD)(P)H: quinone oxidoreductase 1 (NQO1) upregulation, and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) downregulation. Using the human OSCC cell lines HSC3 and HSC4, we demonstrate that HOXA11-AS promotes NQO1 expression by sponging microRNA-494. In contrast, HOXA11-AS recruits zeste homolog 2 (EZH2) to the NQO2 promoter to suppress its expression via the trimethylation of H3K27. The upregulation of NQO1 enzymatic activity by HOXA11-AS results in the consumption of flavin adenine dinucleotide (FAD), which reduces FAD-requiring glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity and suppresses glycolysis. However, our analyses show that lactic acid fermentation levels are preserved by glutaminolysis due to increased malic enzyme-1 expression, promoting enhanced proliferation, invasion, survival, and drug resistance. In contrast, suppression of NQO2 expression reduces the consumption of NRH via NQO2 enzymatic activity and increases NAD levels, which promotes enhanced stemness and metastatic potential. In mouse tumor models, knockdown of HOXA11-AS markedly suppressed tumor growth and lung metastasis. From these findings, targeting HOXA11-AS may strongly suppress high-grade OSCC by regulating both NQO1 and NQO2.

Abstract Background Long non-coding RNAs (lncRNAs) are promising therapeutic molecules of cancer. Here we aim to study the therapeutic effect and mechanism of a lncRNA, HOXA11-AS, in oral squamous cell carcinoma (OSCC). Methods OSCC tissues and adjacent matched paraneoplastic normal tissues used in this study were collected from 42 OSCC patients. The significant downregulation or upregulation of HOXA11-AS expression in OSCC cells was confirmed by quantitative real-time PCR (qRT-PCR). Bioinformatics analysis of StarBase were performed to investigate the potential microRNAs mediated by HOXA11-AS. HOXA11-AS-transfected cells or control cells were subcutaneously injected into nude mice to further determine the effects of HOXA11-AS on OSCC progression in vivo. Results qRT-PCR analysis indicated that HOXA11-AS expression was significantly upregulated in OSCC tissues. Functional studies revealed that HOXA11-AS significantly promotes cell proliferation, reduces the percentage of G0/G1 phase cells and enhances the cell invasion in OSCC. Bioinformatics analysis suggested that a microRNA (miRNA), miR-518a-3p, is as a target of HOXA11-AS. Alteration of miR-518a-3p levels by HOXA11-AS transduced to changes in PDK1 expression. In a mouse model of OSCC, HOXA11-AS overexpression promoted tumor growth, concomitant with reduced miR-518a-3p expression and increased PDK1 expression. Conclusion Taken together, our study demonstrates that HOXA11-AS/miR-518a-3p/PDK1 axis is an important regulator of OSCC progression and may serve as a potential therapeutic target in OSCC. HARMU20150128, registered at Jan, 28 2018.

Kun Cao,1 Yueyang Fang,1 Hao Wang,1 Zheng Jiang,1 Li Guo,2 Yong Hu11Department of Orthopaedics, The First Hospital Of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Orthopaedics, The Second Hospital Of Shanxi Medical University, Taiyuan, People’s Republic of ChinaObjective: Many studies have shown that long non-coding RNAs (lncRNAs) are closely related to various cancers. This study aims to explore the roles of lncRNA HOXA11-AS in the development and progression of osteosarcoma (OS).Methods: The expression levels of HOXA11-AS and miR-125a-5p in tumor tissues and the adjacent tissues were detected by RT-PCR method. The proliferation, migration and invasion of MG-63 and KHOS cells were determined.Results: It was found that HOXA11-AS expression levels in OS tissues and OS cell lines were higher than those in OS adjacent tissues and normal human osteoblast cell lines. The higher expression level of HOXA11-AS was positively correlated with more severe clinical stage, distant metastasis and poor prognosis of OS. Inhibition of HOXA11-AS expression could reduce metastasis and invasion of OS cell lines. In addition, HOXA11-AS was found to be an endogenous inhibitor of miR-125a-5p, it down regulated the expression level of miR-125a-5p, and this process could promote the expression of Rab3D, the target gene of miR-125a-5p.Conclusion: Our study elucidated the role of a new HOXA11-AS/miR-125a-5p/Rab3D regulatory pathway in promoting OS metastasis.Keywords: osteosarcoma (OS), long non-coding RNAs (lncRNAs), HOXA11-AS, miR-125a-5p, Rab3D

Glioblastoma (GB) is by far the most hostile type of malignant tumor that primarily affects the brain and spine, derived from star-shaped glial cells that are astrocytes and oligodendrocytes. Despite of significant efforts in recent years in glioblastoma research, the clinical efficacy of existing medical intervention is still limited and very few potential diagnostic markers are available. Long non-coding RNAs (lncRNAs) that lacks protein-coding capabilities were previously thought to be “junk sequences” in mammalian genomes are quite indispensible epigenetic regulators that can positively or negatively regulate gene expression and nuclear architecture, with significant roles in the initiation and development of tumors. Nevertheless, the precise mechanism of these distortedly expressed lncRNAs in glioblastoma pathogenesis is not yet fully understood. Since the advent of high-throughput sequencing technologies, more and more research have elucidated that lncRNAs are one of the most promising prognostic biomarkers and therapeutic targets for glioblastoma. In this paper, I briefly outlined the existing findings of lncRNAs. And also summarizes the profiles of different lncRNAs that have been broadly classified in glioblastoma research, with emphasis on both their prognostic and therapeutic values.

Keloid is troublesome for patients' skin appearance and mental health, although it is a benign tumor. Long noncoding RNA (lncRNA) troubling keloid is frequently reported. The purpose of this study was to investigate the role of lncRNA homeobox (HOX) A11 antisense (HOXA11-AS) and related action mechanisms during the development of keloid. The expression of HOXA11-AS, miR-205-5p, and forkhead box M1 (FOXM1) was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation or apoptosis was assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium (MTT) assay or flow cytometry assay. Cell migration and invasion were monitored by transwell assay. The protein levels of extracellular matrix (ECM) proteins (collagen I and collagen III), fibronectin, glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and FOXM1 were quantified by Western blot. Glycolysis processes were investigated by the glycolysis stress test, glucose consumption, and lactate production. The relationship between miR-205-5p and HOXA11-AS or FOXM1 was predicted by the online tool MIRcode or starBase v2.0 and verified by dual-luciferase reporter assay or RNA immunoprecipitation (RIP). HOXA11-AS and FOXM1 were significantly upregulated in keloid tissues and keloid fibroblasts, while miR-205-5p was downregulated. HOXA11-AS knockdown or miR-205-5p enrichment inhibited proliferation, migration, invasion, ECM accumulation, and glycolysis but accelerated apoptosis of keloid fibroblasts. MiR-205-5p was targeted by HOXA11-AS, and its inhibition overturned the effects of HOXA11-AS knockdown. Moreover, FOXM1 was a target of miR-205-5p, and HOXA11-AS regulated the expression of FOXM1 by adsorbing miR-205-5p. FOXM1 overexpression abolished the role of miR-205-5p enrichment. The HOXA11-AS-miR-205-5p-FOXM1 pathway may be an active mode in which HOXA11-AS participates in the progression of keloid. [ABSTRACT FROM AUTHOR]

Objective To analyze the prognosis-related differentially expressed long non-coding RNAs（lncRNAs） in the head and neck squamous cell carcinoma（HNSCC）tissues by using bioinformatics methods，to construct their com⁃ peting endogenous RNAs（ceRNA）networks, and to analyze their biological functions. Methods The differentially ex⁃ pressed lncRNAs in the HNSCC and control tissues were screened in the cancer genome atlas（TCGA）database by using P <0. 05 and |log2FC >1. 0 as the criteria. Kaplan-Meier Plotter survival analysis was performed to select the most diagnostic lncRNA which was unreported before and had diagnostic potential，the ceRNA network was constructed by using starBase online website，and gene ontology（GO）and Kyoto gene and genome encyclopedia（KEGG）were used to analyze their biological functions. Results One hundred and twenty-nine differentially expressed lncRNAs were screened out. HOXA11- AS was selected as a candidate lncRNA. HOXA11-AS interacted with 4 differentially expressed microRNAs（miRNAs）and 12 differentially expressed messenger RNAs（mRNAs). The biological functions were mainly enriched in the cellular response to endogenous stimuli, negative regulation of messenger ribonucleoprotein complexes and cytoplasmic translation；the signaling pathways involved were mainly reproduction-related pathways such as dorsoventral axis formation and progesterone-mediated oocyte maturation，fat metabolism-related pathways and cancer-related pathways. Conclusions We screen out the candidate lncRNA（HOXA11-AS) related to the prognosis of HNSCC，and construct a ceRNA regulatory network by taking HOXA11-AS as the center. HOXA11-AS is involved in biological functions such as cellular responses to endogenous stimuli，and the signaling pathways involved are mainly reproduction，lipid metabolism，and cancer-related pathways. [ABSTRACT FROM AUTHOR]

LncRNA HOXA11-AS functions as regulator of tumorigenesis of several human cancers. The present study was intended to explore its regulatory control in human skin cancer with emphasis on understanding the underlying molecular mechanism. The results showed significant (P < 0.05) upregulation of lncRNA HOXA11-AS transcript levels in human skin cancer tissues and cell lines. The knockdown of HOXA11-AS significantly (P < 0.05) inhibited the proliferation and colony formation of A375 and HMCB skin cancer cells. Flow cytometry showed that HOXA11-AS knockdown triggered arrest of the A375 and HMCB cells at G2/M check point of cell cycle by inhibiting the expression of cyclin B1. Additionally, western blot analysis showed that HOXA11-AS knockdown resulted in the deactivation of PI3K/AKT/mTOR signaling pathway. The silencing of HOXA11-AS significantly (P < 0.05) inhibited the migration and invasion of the A375 and HMCB skin cancer cells. This was also accompanied by increase in E-cadherin and decrease in N-cadherin expression. Collectively, the results indicate that lncRNA HOXA11-AS regulates the proliferation, migration and invasion of human skin cancer and may exhibit therapeutic potential in the treatment of skin cancer. [ABSTRACT FROM AUTHOR]

Background: Homeobox (HOX) A11 antisense RNA (HOXA11-AS) has been identified as a cancer promoting lncRNA and is overexpressed in nephroblastoma. However, how HOXA11-AS is regulated in a hypoxic inflammatory environment has not been studied., Methods: In this study, gene expression and epithelial-mesenchymal transition (EMT) ability were detected in the nephroblastoma cell line WiT49 under conditions of hypoxia and inflammation. Next, HOXA11-AS transcription factors were predicted by datasets and subsequently confirmed by CHIP-QPCR, EMSA, and dual-luciferase reporter assays. Moreover, the regulatory relationships of HOXA11-AS and its transcription factors were further confirmed by rescue experiments., Results: Our results showed that a hypoxic microenvironment promoted HOXA11-AS expression and nephroblastoma progression, induced EMT, and activated the Wnt signaling pathway. Combined hypoxia and inflammation had a more substantial effect on nephroblastoma than either hypoxia or inflammation alone. HIF-1α and C/EBPβ were confirmed to be the transcription factors for HOXA11-AS. Silencing of HIF-1α or C/EBPβ downregulated HOXA11-AS expression and suppressed EMT and the Wnt signaling pathway in nephroblastoma cells exposed to a hypoxic or inflammatory microenvironment. HOXA11-AS overexpression partly reversed the effect of HIF-1α or C/EBPβ knockdown., Conclusion: We demonstrated that hypoxia/inflammation-induced upregulation of HIF-1α and C/EBPβ promoted nephroblastoma EMT by improving HOXA11-AS transcription. HOXA11-AS might be a therapy target for nephroblastoma., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

To elucidate the mechanism of action of HOXA11-AS in modulating the cisplatin resistance of nasopharyngeal carcinoma (NPC) cells. HOXA11-AS and miR-454-3p expression in NPC tissue and cisplatin-resistant NPC cells were measured via quantitative reverse transcriptase polymerase chain reaction. NPC parental cells (C666-1 and HNE1) and cisplatin-resistant cells (C666-1/DDP and HNE1/DDP) were transfected and divided into different groups, after which the MTT method was used to determine the inhibitory concentration 50 (IC50) of cells treated with different concentrations of cisplatin. Additionally, a clone formation assay, flow cytometry and Western blotting were used to detect DDP-induced changes. Thereafter, xenograft mouse models were constructed to verify the in vitro results. Obviously elevated HOXA11-AS and reduced miR-454- 3p were found in NPC tissue and cisplatin-resistant NPC cells. Compared to the control cells, cells in the si-HOXA11- AS group showed sharp decreases in cell viability and IC50, and these results were reversed in the miR-454-3p inhibitor group. Furthermore, HOXA11-AS targeted miR-454-3p, which further targeted c-Met. In comparison with cells in the control group, HNE1/DDP and C666-1/DDP cells in the si- HOXA11-AS group demonstrated fewer colonies, with an increase in the apoptotic rate, while the expression levels of c-Met, p-Akt/Akt and p-mTOR/mTOR decreased. Moreover, the si-HOXA11-AS-induced enhancement in sensitivity to cisplatin was abolished by miR-454-3p inhibitor transfection. The in vivo experiment showed that DDP in combination with si-HOXA11-AS treatment could inhibit the growth of xenograft tumors. Silencing HOXA11-AS can inhibit the c-Met/AKT/mTOR pathway by specifically upregulating miR- 454-3p, thus promoting cell apoptosis and enhancing the sensitivity of cisplatin-resistant NPC cells to cisplatin. [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma (OSCC) is a type of oral malignancy. Long non-coding RNAs (lncRNAs) have been shown to be related to the occurrence and development of many cancers. Here, we aimed to study the role and molecular mechanism of lncRNA Homeobox A11 antisense RNA (HOXA11-AS) in OSCC. Methods: The expression levels of HOXA11-AS, miR-98-5p and Y box binding protein 2 (YBX2) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell counting kit-8 (CCK-8), flow cytometry and transwell assays were utilized to determine the proliferation, apoptosis, migration and invasion of OSCC cells. Western blot (WB) analysis was conducted to measure the levels of apoptosis, epithelial-mesenchymal transition (EMT), proliferation-related proteins and YBX2 protein. Besides, Dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull down assays were carried out to examine the relationship among HOXA11-AS, miR-98-5p and YBX2. The mice xenograft models were constructed to further determine the effect of HOXA11-AS on OSCC tumor growth in vivo. Results: HOXA11-AS was highly expressed in OSCC tissues and cells. Knockdown of HOXA11-AS significantly reduced proliferation, migration, invasion and EMT, while promoted apoptosis of OSCC cells. MiR-98-5p was a target of HOXA11-AS, and its inhibitor could revert the inhibition effect of silenced-HOXA11-AS on the progression of OSCC. Also, YBX2 was a target of miR-98-5p, and its overexpression could invert the suppression effect of miR-98-5p overexpression on the progression of OSCC. YBX2 expression was regulated by HOXA11-AS and miR-98-5p. Furthermore, HOXA11-AS silencing could reduce the tumor growth of OSCC in vivo. Conclusion: HOXA11-AS plays an active role in the progression of OSCC, and the discovery of HOXA11-AS/miR-98-5p/YBX2 axis provides new therapeutic targets for OSCC.

Jiang-yang Xue,1 Chao Huang,2 Wei Wang,1 Hai-bo Li,1 Ming Sun,3 Min Xie2 1Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China; 2Central Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, Jiangsu, China; 3Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA Abstract: Multiple studies have demonstrated that lncRNAs extensively participate in human cancer proliferation and metastasis. Epigenetic modification, transcriptional and posttranscriptional regulatory mechanisms are involved in lncRNA-led tumorigenesis and transfer. Recently, a novel identified homeobox (HOX) A11 antisense lncRNA, HOXA11-AS, 1,628 bp in length, has been excessively highlighted to be an essential initiator and facilitator in the process of malignant tumor proliferation and metastasis. As found in many reports, HOXA11-AS can not only act as a molecular scaffold of PRC2, LSD1 and DNMT1 to epigenetically modify chromosomes in the nucleus but also occur as ceRNA competitively sponging miRNAs in the cytoplasm. Furthermore, HOXA11-AS may function as a potential biomarker for cancer diagnosis and prognosis. In this review, we summarize the evolvement and mechanisms of HOXA11-AS in proliferation and metastasis of various human cancers. Keywords: HOXA11-AS, proliferation, metastasis, EMT, ceRNA, lncRNA, molecular scaffold

Abstract Background Recent studies have emphasized the important prognostic role of long noncoding RNAs (lncRNAs) in various types of cancers. Here we conducted a meta-analysis to investigate whether lncRNA HOXA11-AS can be served as a prognostic biomarker in human cancers. Patients/methods We systematically searched PubMed, Embase, ISI Web of Science, and SCOPUS for relevant studies, to investigate the prognostic significance of HOXA11-AS expression in cancer patients. Odds ratios (ORs) or hazards ratios (HRs) with corresponding 95% confidence intervals (CIs) are pooled to estimate the association between HOXA11-AS expression and clinicopathological parameters or survival of cancer patients. Results A total of eight eligible studies with 1320 cancer patients were enrolled in our meta-analysis. The results revealed that increased expression level of HOXA11-AS was significantly associated with clinicopathological parameters including more lymph node metastasis (OR = 2.06, 95% CI 1.31–3.25), advanced tumor stage (OR = 4.22, 95% CI 2.60–6.85), as well as poor tumor differentiation (OR = 2.49, 95 CI 1.47–4.20), but not correlated with age (p = 0.101) or gender (p = 0.845). In addition, cancer patients with high HOXA11-AS are prognosed to have shorter OS (pooled HR = 1.86, 95% CI 1.39–2.48) and PFS (pooled HR = 2.47, 95% CI 1.29–4.75). Conclusions HOXA11-AS overexpression might be a convinced unfavorable prognostic factor that helps the clinical decision-making process.

Increasing researches have focused on the biological functions of long noncoding RNAs (lncRNAs) in human cancers. HOXA11-AS, a widely known lncRNA, has been confirmed to be involved in the progression of several cancers, including gastric cancer (GC). Whereas, the detailed mechanism of this lncRNA in GC remains to be further illuminated. The abundances of HOXA11-AS, miR-148a and WNT1 in GC tissues and cell lines were examined by qRT-PCR. Clinicopathological and Kaplan-Meier survival analyses were determined to explore the relationship between HOXA11-AS expression and outcomes of patients. Transwell assay was performed for the evaluation of cell migration and invasion. Bioinformatics, dual-luciferase reporter and RNA immunoprecipitation assays were employed to analyze the correlation between HOXA11- AS and miR-148a or miR-148a and WNT1. The protein levels of WNT1 and ß-catenin were assessed by western blot assay. Results showed that HOXA11-AS and WNT1 expression levels were upregulated, while miR-148a level was downregulated in GC tissues and cell lines relative to matched controls. Elevated expression of HOXA11-AS was associated with increased tumor size, lymph node metastasis, advanced TNM stage, as well as reduced survival of GC patients. HOXA11-AS induced migration and invasion of GC cells through serving as a molecular sponge for miR-148a. Furthermore, miR-148a inactivated WNT1/ß-catenin signaling pathway via directly targeting WNT1. HOXA11-AS increased WNT1/ß-catenin pathway activity, which was abolished by miR-148a overexpression in GC cells. In conclusion, overexpression of HOXA11-AS contributed to migration and invasion of GC cells via activation of WNT1/ß-catenin signaling pathway through repressing miR-148a, providing a prospective therapeutic target for GC. [ABSTRACT FROM AUTHOR]

Hypopharyngeal squamous cell carcinoma (HSCC) remains one of the most lethal malignancies in the head and neck. Long noncoding RNA (lncRNA) HOXA11-AS is proven to function as an oncogene and a therapeutic target in various tumors. Our previous study and others have demonstrated that HOXA11-AS is one of the most upregulated lncRNAs in HSCC. However, the role of HOXA11-AS in HSCC has not yet been identified. The current study demonstrated that the expression of HOXA11-AS was significantly upregulated in HSCC tumors and was positively associated with lymph node metastasis. Moreover, functional experiments revealed that HOXA11-AS knockdown suppressed the proliferation and migration potential in FaDu cells. Furthermore, luciferase reporter gene assay combined with cellular functional experiments demonstrated that HOXA11-AS functioned as a molecular sponge for miR-155, and inhibition of miR-155 attenuated the suppressive effect of HOXA11-AS knockdown on the aggressive phenotype in HSCC. This study identifies a tumor-promoting role of HOXA11-AS in HSCC and suggests HOXA11-AS might be a potential diagnostic and therapeutic target for HSCC. [ABSTRACT FROM AUTHOR]

Long noncoding RNA (lncRNA) has been suggested to play an important role in a variety of diseases over the past decade. In a previous study, we identified a novel lncRNA, termed HOXA11‐AS, which was significantly up‐regulated in calcium oxalate (CaOx) nephrolithiasis. However, the biological function of HOXA11‐AS in CaOx nephrolithiasis remains poorly defined. Here, we demonstrated that HOXA11‐AS was significantly up‐regulated in CaOx nephrolithiasis both in vivo and in vitro. Gain‐/loss‐of‐function studies revealed that HOXA11‐AS inhibited proliferation, promoted apoptosis and aggravated cellular damage in HK‐2 cells exposed to calcium oxalate monohydrate (COM). Further investigations showed that HOXA11‐AS regulated monocyte chemotactic protein 1 (MCP‐1) expression in HK‐2 cell model of CaOx nephrolithiasis. In addition, online bioinformatics analysis and dual‐luciferase reporter assay results showed that miR‐124‐3p directly bound to HOXA11‐AS and the 3'UTR of MCP‐1. Furthermore, rescue experiment results revealed that HOXA11‐AS functioned as a competing endogenous RNA to regulate MCP‐1 expression through sponging miR‐124‐3p and that overexpression of miR‐124‐3p restored the inhibitory effect of proliferation, promotion effects of apoptosis and cell damage induced by HOXA11‐AS overexpression. Taken together, HOXA11‐AS mediated CaOx crystal–induced renal inflammation via the miR‐124‐3p/MCP‐1 axis, and this outcome may provide a good potential therapeutic target for nephrolithiasis. [ABSTRACT FROM AUTHOR]

HOXA11, which is a member of the homeobox (HOX) gene family, and its natural antisense transcript (NAT) HOXA11-AS have been reported to be closely related to the development of lung cancer. We aimed to investigate their specific roles in cisplatin (DDP) resistance in lung adenocarcinoma (LUAD). First, we found that HOXA11 is hypermethylated and significantly downregulated in a DDP-resistant A549 cell line (A549/DDP) and LUAD tissues, while the HOXA11-AS expression level is elevated. Although HOXA11 and HOXA11-AS mRNA overlap in the 5ʹ-untranslated region (5ʹ UTR) and share two CpG islands, DNA methylation only regulates the expression of HOXA11. Then, we found that HOXA11 and HOXA11-AS have an inverse interaction by transfecting their siRNAs and overexpression vectors into A549 and A549/DDP cells. A dual-luciferase reporter assay further confirmed that the overlapping 5ʹUTR is essential for the bidirectional regulation between HOXA11 and HOXA11-AS. Functional analysis showed that knockdown of HOXA11 expression in A549 cells induced DDP resistance and activated Akt/β-catenin signaling, while overexpression of HOXA11 in A549/DDP cells increased DDP sensitivity and inhibited Akt/β-catenin signaling. Moreover, HOXA11-AS knockdown in A549 cells increased DDP sensitivity and inhibited Akt/β-catenin signaling, while the overexpression of HOXA11-AS in A549/DDP cells induced DDP resistance and activated Akt/β-catenin signaling. In conclusion, our study demonstrates that the inverse interaction between HOXA11 and HOXA11-AS promotes DDP resistance in LUAD. [ABSTRACT FROM AUTHOR]

The objective of this study was to examine the function of the long non-coding RNA (lncRNA) HOXA11-AS in hepatocellular carcinoma (HCC). In total, samples from liver tumor and surrounding normal liver tissues were collected from 66 cases of HCC patients. Normal liver cell line HL-7702 and HCC cell lines HepG2, Hep3B, MHCC-97H and BEL7402 were used. Cells were transfected with different small interference RNAs or vectors. Then, transwell assay, qRT-PCR, CHIP, RIP and Western blot experiments were performed. We found that the HOXA11-AS expression level was higher in HCC samples than surrounding normal liver tissues. And the higher expression level of HOXA11-AS in HCC patients indicated a lower 5-year survival rate. Knockdown of HOXA11-AS in HepG2 and Hep3B cells caused impaired cell invasion and migration abilities. Otherwise, upregulation of HOXA11-AS in MHCC-97H and BEL7402 cells displayed higher invasion and migration capabilities. We also demonstrated that HOXA11-AS could inhibit miR-124 expression by binding to EZH2. Furthermore, overexpression of miR-124 or knockdown EZH2 expression could reverse the HOXA11-AS-induced migration and invasion effects in HCC cells. In summary, the high HOXA11-AS expression in HCC patients is associated with the poor outcome. HOXA11-AS could inhibit miR-124 expression by binding to EZH2 and thus promoted the migration and invasion of HCC cells. [ABSTRACT FROM AUTHOR]

Abstract Background Glioma stem cells (GSCs) represent a subpopulation of cells within glioma that are characterized by chemotherapy resistance and tumor recurrence. GSCs are therefore important therapeutic target for glioma therapy. Long non-coding RNAs (lncRNAs) have been shown to regulate important functions in cancer. HOXA11-AS is one such lncRNA and has been shown to regulate cell proliferation via promotion of cell cycle progression in glioblastoma (GBM) cells. However, the specific roles of HOXA11-AS in GSCs remain unclear. Methods Here we investigated the role of HOXA11-AS in driving GSC stemness properties via sphere-forming and protein chip assays. Results Gain-of-function as well as loss-of-function results showed that the HOXA11-AS maybe a critical modulator in GBM recurrence as demonstrated by cell sphere-forming ability. Furthermore, we showed that induced expression of HOXA11-AS does increase the levels of stemness-related transcription factors (Oct4/Sox17/Sox2) in U87MG cells. In vivo xenograft experiments using the HOXA11-AS knockdown U87MG cells revealed that downregulation of HOXA11-AS could strongly inhibit tumor growth. Furthermore, we found that HOXA11-AS knockdown decreased the expression of cancer stemness markers in vivo. Conclusions Collectively, these data suggests that HOXA11-AS is involved in GSC stemness and supports its clinical significance as a important therapeutic target in glioma.

Abstract Background Recent studies have verified that long noncoding RNAs (lncRNAs) involved in many biological functions and play crucial roles in human cancers progression, the study aimed to detect the association between long non-coding RNA HOXA11-AS and epithelial–mesenchymal transition (EMT) process in non-small cell lung cancer (NSCLC). Methods The lncRNA HOXA11-AS expression levels were determined by quantitative real-time polymerase chain reaction (qRT-PCR) assays in 78 paired of tumor tissue and adjacent normal tissue samples in NSCLC patients. Kaplan–Meier survival curves and log-rank test was used to examine the association between lncRNA HOXA11-AS expression and the over survival time in NSCLC patients. Transwell invasion assay was performed to detect the cell invasion ability. QRT-PCR and western-blot analysis detected the mRNA and protein expression of EMT related transcription factors ZEB1/ZEB2, Snail1/2 and EMT marker E-cadherin and N-cadherin in NSCLC cells. RIP and Chromatin immunoprecipitation assays were performed to analyze the association between lncRNA HOXA11-AS and miR-200b expression in NSCLC cells. Results The lncRNA HOXA11-AS expression levels were significantly higher in NSCLC tissues compared with adjacent normal tissues and higher HOXA11-AS expression levels had a poor prognosis in NSCLC patients. Furthermore, knockdown of lncRNA HOXA11-AS in A549 and H1299 cells dramatically inhibited cell invasive abilities. Besides, the transcription levels and protein levels of EMT related transcription factors ZEB1/ZEB2, Snail1/2, and EMT maker N-cadherin were down-regulated after lncRNA HOXA11-AS was knocked down, but the mRNA and protein expression levels of EMT maker E-cadherin was increasing in A549 and H1299 cells. The mechanistic findings showed demonstrated that HOXA11-AS interacted with EZH2 and DNMT1 and recruited them to the miR-200b promoter regions to repress miR-200b expression in NSCLC cells, which promoted cell EMT in NSCLC. Conclusions Our results showed that up-regulation of lncRNA HOXA11-AS predicted a poor prognosis and lncRNA HOXA11-AS promoted cell epithelial–mesenchymal transition (EMT) by inhibiting miR-200b expression in NSCLC.

Abstract Background Long noncoding RNAs (lncRNAs) have emerged as critical regulators in a variety of human cancers, including gastric cancer (GC). However, the function and mechanisms responsible for these molecules in GC are not fully understood. In our previous study, we found that GC associated lncRNA HOXA11-AS is significantly upregulated in GC tissues. Over-expressed HOXA11-AS promotes GC cells proliferation and invasion through scaffolding the chromatin modification factors PRC2, LSD1 and DNMT1. Methods HOXA11-AS expression levels in GC cells was detected by quantitative real-time PCR (qPCR). HOXA11-AS siRNAs and overexpression vector were transfected into GC cells to down-regulate or up-regulate HOXA11-AS expression. In vitro and in vivo assays were performed to investigate the functional role of HOXA11-AS in GC cells cell cycle progression, invasion and metastasis. RIP and ChIP assays were used to determine the mechanism of HOXA11-AS’s regulation of underlying targets. Results We found that knockdown of HOXA11-AS induced GC cells G0/G1 phase arrest and suppressed GC cells migration, invasion and metastasis in vivo. Moreover, mechanistic investigation showed that HOXA11-AS could interact with WDR5 and promote β-catenin transcription, bind with EZH2 and repress P21 transcription, and induce KLF2 mRNA degradation via interacting with STAU1. Conclusions Taken together, these findings show that HOXA11-AS not only could promote GC cells migration and invasion in vitro, but also promotes GC cells metastasis in vivo, at least in part, by regulating β-catenin and KLF2.

Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression, which play fundamental roles in cancer development. In this study, we found that homeobox A11 antisense RNA (HOXA11-AS), a highly expressed lncRNA in cell lines derived from prostate cancer bone metastases, promoted the cell invasion and proliferation of PC3 prostate cancer cells. Transcription factor homeobox B13 (HOXB13) was identified as an upstream regulator of HOXA11-AS.HOXA11-AS regulated bone metastasis-associated C-C motif chemokine ligand 2 (CCL2)/C-C chemokine receptor type 2 (CCR2) signaling in both PC3 prostate cancer cells and SaOS2 osteoblastic cells. The HOXB13/HOXA11-AS axis also regulated integrin subunits (ITGAV and ITGB1) specific to prostate cancer bone metastasis. HOXB13, in combination with HOXA11-AS, directly regulated the integrin-binding sialoprotein (IBSP) promoter. Furthermore, conditioned medium containing HOXA11-AS secreted from PC3 cells could induce the expression of CCL2 and IBSP in SaOS2 osteoblastic cells. These results suggest that prostate cancer HOXA11-AS and HOXB13 promote metastasis by regulation of CCL2/CCR2 cytokine and integrin signaling in autocrine and paracrine manners.

OBJECTIVE: Long noncoding RNAs (lncRNAs) serve as important regulators of diverse types of cancer, including glioma. Nevertheless, their precise roles in cancers remain sufficiently unexplored. PATIENTS AND METHODS: Quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) was used to determine the levels of HOMEOBOX A11 antisense RNA (HOXA11-AS) and miR-130a-5p in glioma tissues and cell lines. Short hairpin RNAs (shRNAs) targeting HOXA11- AS or pcDNA3.1 were transfected into cells via a vector encoding HOXA11-AS to decrease or increase the level of HOXA11-AS. Cell Counting Kit-8 (CCK-8), colony formation, wound healing, flow cytometry and transwell assays were applied to assess the role of HOXA11-AS in glioblastoma cell growth, apoptosis and aggressiveness. The expression of N-cadherin and E-cadherin was determined using immunofluorescence staining. The expression of high-mobility group protein B2 (HMGB2) was determined using Western blot analysis in vitro and immunohistochemistry (IHC) staining in vivo. The direct target of HOXA11-AS and miR-130a-5p was confirmed using the Luciferase reporter assay. Glioblastoma cells were subcutaneously implanted into nude mice to determine the role of HOXA11- AS in tumor growth in vivo. RESULTS: In the current study, we demonstrated that the lncRNA HOXA11-AS was overexpressed in glioma. The overexpression of HOXA11-AS was correlated with advanced stages of glioma and poor prognosis. Downregulating HOXA11-AS expression significantly suppressed the proliferation, migration and invasion of glioma cells and increased their apoptosis. The growth of glioma cells in vitro was also suppressed by the downregulation of HOXA11-AS. Finally, we revealed that HOXA11-AS exerted its oncogenic effects by binding to miR-130a-5p, thereby neutralizing the suppressive effect of miR-130a-5p on HMGB2. CONCLUSIONS: Our results demonstrate that HOXA11-AS regulates the growth and metastasis of glioma by targeting the miR-130a-5p- HMGB2 signaling axis. [ABSTRACT FROM AUTHOR]

Recently, increasing studies showed that long noncoding RNAs (lncRNAs) play critical roles in tumor progression. However, the function and underlying mechanism of HOMEOBOX A11 antisense RNA (HOXA11‐AS) on renal cancer remain unclear. In the current study, our data showed that the expression of HOXA11‐AS was significantly upregulated in clear cell renal cell carcinoma (ccRCC) tissues and cell lines. High HOXA11‐AS expression was associated with the advanced clinical stage, tumor stage, and lymph node metastasis. Function assays showed that HOXA11‐AS inhibition significantly suppressed renal cancer cells growth, invasion, and ETM phenotype. In addition, underlying mechanism revealed that HOXA11‐AS could act as a competing endogenous RNA (ceRNA) that repressed miR‐146b‐5p expression, which regulated its downstream target MMP16 in renal cancer. Taken together, our findings suggested that HOXA11‐AS could promote renal cancer cells growth and invasion by modulating miR‐146b‐5p–MMP16 axis. Thus, our findings suggested that HOXA11‐AS could serve as potential therapeutic target for the treatment of renal cancer. HOMEOBOX A11 antisense RNA could promote renal cancer cells growth and invasion by modulating miR‐146b‐5p–MMP16 axis [ABSTRACT FROM AUTHOR]