Cancer-associated Fibroblasts-derived Exosomes with HOXD11 Overexpression Promote Ovarian Cancer Cell Angiogenesis Via FN1.

Cancer-associated fibroblasts (CAFs) represent a critical stromal component of metastatic niche and promote metastasis in patients with ovarian cancer (OC). Here, we try to further understand the mechanism by which CAFs-derived exosomes (CAFs-Exo) promoted angiogenesis in OC. We intersected differentially expressed genes in OC cells after CAFs-Exo treatment in the GSE147610 dataset with a list of transcription factors to identify homeobox protein hox-D11 (HOXD11) as a possible cargo of CAFs-Exo. HOXD11 encapsulated by CAFs-Exo enhanced colony formation, migration, and invasion of OC cells. HOXD11 bound to the promoter of fibronectin (FN1) and promoted its transcription. HOXD11 knockdown from CAFs-Exo significantly repressed the VEGF and CD31 protein expression and tube formation, viability, and migration of human umbilical vein endothelial cells (HUVEC) and slowed angiogenesis and tumor growth in mice. Furthermore, we found that overexpression of FN1 increased the expression of angiogenic factors and activity of HUVEC in the presence of HOXD11 knockdown. These results verify the significant contribution of CAFs-Exo to angiogenesis in OC, which could be partially due to the promotion of FN1 mediated by HOXD11.

HOXD12 defines an age-related aggressive subtype of oligodendroglioma.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR < 0.01, FDR = 1e-5) and the CGGA (p = 0.03, p < 1e-3). HOXD12 gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (p < 1e-6, p < 0.001, p < 1e-3) and with older age and higher WHO grade in Capper et al. (p < 0.002, p = 0.014). In the TCGA, HOXD12 gene body hypermethylation and elevated expression were independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with HOXD12 gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.

Hsa_circ_0000825 promotes the progression of laryngeal squamous cell carcinoma by sponging miR-766 and interacting with ELAVL1.

Emerging evidence suggests that circular RNAs (circRNAs) are involved in the regulation of tumourigenesis and progression of a variety of malignant tumours. In this study, we aimed to identify laryngeal squamous cell carcinoma (LSCC)-specific circRNAs and explore their biological functions and underlying molecular mechanisms. Employing microarray and qRT-PCR, hsa_circ_0000825 was found to be significantly increased in LSCC tissues versus para-cancerous tissues. High hsa_circ_0000825 expression was positively associated with advanced clinical stages, lymph node metastasis, and poor survival. Furthermore, the overexpression of hsa_circ_0000825 in TU177 and AMC-HN-8 cells promoted cell proliferation. Transwell assays showed enhanced migration and invasion of TU177 and AMC-HN-8 cells upon overexpression of hsa_circ_0000825. Conversely, the knockdown of hsa_circ_0000825 had the opposite effect. Xenograft tumours in BALB/c nude mice derived from hsa_circ_0000825-overexpressed TU177 cells showed greater volume and weight than those derived from control TU177 cells. Mechanistically, nuclear-cytoplasmic fractionation assay confirmed that hsa_circ_0000825 was mainly located in the cytoplasm of TU177 and AMC-HN-8 cells. The AGO2-RNA immunoprecipitation (RIP) assay revealed that hsa_circ_0000825 was significantly enriched in the AGO2-precipitated complex in both TU177 and AMC-HN-8 cells, suggesting that this circRNA may function via a competitive endogenous RNA (ceRNA) mechanism. Next, bioinformatics analysis, biotinylated-oligo pull-down assay and dual-luciferase reporter assay verified that miR-766 could be sponged by hsa_circ_0000825 and also target 3'UTR of HOXD10 mRNA. Moreover, miR-766 was shown to be involved in the pro-oncogenic effect of hsa_circ_0000825. This occurred via the mediation of hsa_circ_0000825-enhanced HOXD10 mRNA by the ceRNA mechanism in TU177 and AMC-HN-8 cells. Besides, RNA-binding protein (RBP) ELAVL1 interacted with hsa_circ_0000825 in TU177 and AMC-HN-8 cells, as revealed through bioinformatics analysis, biotinylated-oligo pull-down assays, and RIP assays. ELAVL1 knockdown decreased cell proliferation by 38 % and 34 % in hsa_circ_0000825-overexpressed TU177 and AMC-HN-8 cells (P < 0.05). Similarly, ELAVL1 was involved in the pro-migration and pro-invasion effects of hsa_circ_0000825 overexpression. In addition, comprehensive analysis of mRNA-seq in hsa_circ_0000825-overexpressed TU177 cells, as well as catRAPID and TCGA databases, suggested that ITGB2, HOXD10, and MTCL1 might be crucial downstream target mRNAs of ELAVL1 in LSCC, participating in the hsa_circ_0000825-ELAVL1 axis pro-oncogenic effect. Taken together, hsa_circ_0000825 plays a pro-oncogenic role in LSCC via the miR-766/HOXD10 axis and ELAVL1 and may serve as a promising specific biomarker and therapeutic target for LSCC.

HOXD9 regulated mitophagy to promote endothelial progenitor cells angiogenesis and deep vein thrombosis recanalization and resolution.

BACKGROUND: Deep vein thrombosis (DVT) is a common vascular surgical disease caused by the coagulation of blood in the deep veins, and predominantly occur in the lower limbs. Endothelial progenitor cells (EPCs) are multi-functional stem cells, which are precursors of vascular endothelial cells. EPCs have gradually evolved into a promising treatment strategy for promoting deep vein thrombus dissolution and recanalization through the stimulation of various physical and chemical factors. METHODS: In this study, we utilized a mouse DVT model and performed several experiments including qRT-PCR, Western blot, tube formation, wound healing, Transwell assay, immunofluorescence, flow cytometry analysis, and immunoprecipitation to investigate the role of HOXD9 in the function of EPCs cells. The therapeutic effect of EPCs overexpressing HOXD9 on the DVT model and its mechanism were also explored. RESULTS: Overexpression of HOXD9 significantly enhanced the angiogenesis and migration abilities of EPCs, while inhibiting cell apoptosis. Additionally, results indicated that HOXD9 specifically targeted the HRD1 promoter region and regulated the downstream PINK1-mediated mitophagy. Interestingly, intravenous injection of EPCs overexpressing HOXD9 into mice promoted thrombus dissolution and recanalization, significantly decreasing venous thrombosis. CONCLUSIONS: The findings of this study reveal that HOXD9 plays a pivotal role in stimulating vascular formation in endothelial progenitor cells, indicating its potential as a therapeutic target for DVT management.

The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.

Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.

HOXD10 regulates intestinal permeability and inhibits inflammation of dextran sulfate sodium-induced ulcerative colitis through the inactivation of the Rho/ROCK/MMPs axis.

Ulcerative colitis (UC) has been identified as a severe inflammatory disease with significantly increased incidence across the world. The detailed role and mechanism of HOXD10 in UC remain unclear. In present study, we found that HOXD10 was lowly expressed in UC samples and was notably decreased by dextran sulfate sodium (DSS) administration. Overexpression of HOXD10 dramatically ameliorated DSS-induced UC symptoms, including the loss of weight, increased disease activity index values, and the shortened colon length. Additionally, terminal-deoxynucleoitidyl transferase mediated nick end labeling and immunohistochemistry staining assays showed that HOXD10 overexpression suppressed cell apoptosis and facilitated proliferation of colon tissues after DSS treatment. Moreover, HOXD10 overexpression obviously suppressed DSS-triggered inflammatory response by decreasing the expression level of TNF-α, IL-6, and IL-1ß. Furthermore, overexpression of HOXD10 effectively restored the intestinal permeability, thereby alleviating DSS-induced intestinal barrier dysfunction. Mechanistic study demonstrated that HOXD10 significantly reduced the activities of Rho/ROCK/MMPs axis in colon tissues of mice with UC. In conclusion, this study revealed that HOXD10 might effectively improve DSS-induced UC symptoms by suppressing the activation of Rho/ROCK/MMPs pathway.

POU6F2, a risk factor for glaucoma, myopia and dyslexia, labels specific populations of retinal ganglion cells.

Pou6f2 is a genetic connection between central corneal thickness (CCT) in the mouse and a risk factor for developing primary open-angle glaucoma. POU6F2 is also a risk factor for several conditions in humans, including glaucoma, myopia, and dyslexia. Recent findings demonstrate that POU6F2-positive retinal ganglion cells (RGCs) comprise a number of RGC subtypes in the mouse, some of which also co-stain for Cdh6 and Hoxd10. These POU6F2-positive RGCs appear to be novel of ON-OFF directionally selective ganglion cells (ooDSGCs) that do not co-stain with CART or SATB2 (typical ooDSGCs markers). These POU6F2-positive cells are sensitive to damage caused by elevated intraocular pressure. In the DBA/2J mouse glaucoma model, heavily-labeled POU6F2 RGCs decrease by 73% at 8 months of age compared to only 22% loss of total RGCs (labeled with RBPMS). Additionally, Pou6f2-/- mice suffer a significant loss of acuity and spatial contrast sensitivity along with an 11.4% loss of total RGCs. In the rhesus macaque retina, POU6F2 labels the large parasol ganglion cells that form the magnocellular (M) pathway. The association of POU6F2 with the M-pathway may reveal in part its role in human glaucoma, myopia, and dyslexia.

METTL3 promotes the osteogenic differentiation of periosteum-derived MSCs via regulation of the HOXD8/ITGA5 axis in congenital pseudarthrosis.

Background: Congenital pseudarthrosis of the tibia (CPT) is a dominant health challenge in pediatric orthopedics. The essential process in the development of CPT is the limited capacity of mesenchymal stem cells (MSCs) derived from CPT to undergo osteogenic differentiation. Our research aimed to elucidate the role and mechanism of methyltransferase-like 3 (METTL3) in the osteogenic differentiation process of CPT MSCs. Methods: The osteogenic differentiation medium was used to culture MSCs, and the detection of osteogenic differentiation was performed using Alizarin Red S and alkaline phosphatase (ALP) assays. Gene or protein expression was assessed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, or immunofluorescence (IF) staining. The m6A modification of Homeobox D8 (HOXD8) was verified by methylated RNA immunoprecipitation (MeRIP) assay. Interactions between METTL3 and HOXD8 or HOXD8 and integrin alpha 5 (ITGA5) promoter were validated by the luciferase reporter gene, RIP, and chromatin immunoprecipitation (ChIP) assays. Results: METTL3 overexpression enhanced CPT MSCs' osteogenic differentiation. METTL3 stabilized the HOXD8 in an m6A-dependent manner. Moreover, the overexpressed ITGA5 up-regulated the CPT MSCs' osteogenic differentiation. Further, HOXD8 could transcriptionally activate ITGA5. METTL3 increased the transcription of ITGA5 via HOXD8 to enhance the osteogenic differentiation of CPT MSCs. Conclusion: METTL3 promoted osteogenic differentiation via modulating the HOXD8/ITGA5 axis in CPT MSCs.

The diagnostic potential of miR-196a-1 in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a common malignancy worldwide. MicroRNAs (miRNAs) are important epigenetic alterations that notably impact various physiological and pathological processes by acting as negative regulators of gene expression. Furthermore, they have a vital function in different types of cancers, including CRC. In this research, we evaluated, for the very first time, the expression levels of miR-196a-1 in the tissue and plasma of patients with CRC and also homeobox D8 (HOXD8) as the target gene. MATERIALS AND METHODS: This study included a collection of 220 plasma and tissue samples from 55 patients diagnosed with CRC, as well as 55 healthy individuals matched by age and sex. Total RNA was extracted from plasma and tissue samples, and then polyadenylation and cDNA synthesis were performed. The expression levels of miR-196a-1 and HOXD8 as target gene was evaluated by quantitative RT-PCR (qRT-PCR) assay. We compared the diagnostic value of plasma miR-196a-1 with that of the circulating tumor markers CA19-9 and CEA using a Receiver Operating Characteristics (ROC) analysis. The association of miR-196a-1 with clinicopathological characteristics was assessed in tissue and plasma samples from patients with CRC. RESULTS: Our data demonstrated that the expression levels of miR-196a-1 in the tissue and plasma samples of CRC patients were 11.426- and 11.655-fold higher, respectively than those in adjacent normal tissue and plasma samples from normal subjects (p < 0.001). Through ROC curve analysis, it was identified that the sensitivity and specificity of miR-196a-1 for tissue samples, with an AUC of 0.925, were 89% and 98%, respectively. In addition, the sensitivity and specificity for plasma samples with an AUC of 0.801 were 70% and 98%, respectively. These findings reveal that miR-196a-1 is a useful biomarker for discriminating cases from controls. Furthermore, the expression of HOXD8 was not significantly altered in tumor tissue samples compared to adjacent normal tissues (P > 0.05). CONCLUSIONS: These results show that miR-196a-1 has an oncogenic impact and plays a significant role in CRC development. The results also indicate that miR-196a-1 could serve as a novel noninvasive biomarker for the detection of CRC.

Inhibition of HOXD11 promotes cartilage degradation and induces osteoarthritis development.

The 5'-HOXD genes are important for chondrogenesis in vertebrates, but their roles in osteoarthritis (OA) are still ambiguous. In our study, 5'-HOXD genes involvement contributing to cartilage degradation and OA was investigated. In bioinformatics analysis of 5'-HOXD genes, we obtained the GSE169077 data set related to OA in the GEO and analyzed DEGs using the GEO2R tool attached to the GEO. Then, we screened the mRNA levels of 5'-HOXD genes by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). We discovered that OA chondrocyte proliferation was inhibited, and apoptosis was increased. Moreover, it was discovered that SOX9 and COL2A1 were downregulated at mRNA and protein levels, while matrix metalloproteinases (MMPs) and a disintegrin-like and metalloproteinase with thrombospondin motifs (ADAMTSs) were upregulated. According to the results of differentially expressed genes (DEGs) and qRT-PCR, we evaluated the protein level of HOXD11 and found that the expression of HOXD11 was downregulated, reversed to MMPs and ADAMTSs but consistent with the cartilage-specific factors, SOX9 and COL2A1. In the lentivirus transfection experiments, HOXD11 overexpression reversed the effects in OA chondrocytes. In human OA articular cartilage, aberrant subchondral bone was formed in hematoxylin-eosin (H&E) and Safranin O and fast green (SOFG) staining results. Furthermore, according to immunohistochemistry findings, SOX9 and HOXD11 expression was inhibited. The results of this study established that HOXD11 was downregulated in OA cartilage and that overexpression of HOXD11 could prevent cartilage degradation in OA.

Gene Expression Profile Analysis of the Molecular Mechanism of HOXD10 Regulation of Epithelial Ovarian Cancer Cells.

Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer. Although studies have reported that downregulation of HOXD10 expression may contribute to the migration and invasion abilities in EOC, much about its regulation remains to be fully elucidated. The present study aimed to identify different gene expression profiles associated with HOXD10 overexpression in EOC cells. The present study confirmed that HOXD10 overexpression effectively inhibited the proliferation and motility of the TOV21G and TOV112D cells. Further, we overexpress HOXD10 in TOV112D cells, the different gene expression (DEGs) profiles induce by HOXD10 was analyze by the Human OneArray microarray. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), ingenuity pathway analysis (IPA) was used to perform the pathway enrichment analysis for the DEGs. Integrated bioinformatics analysis showed that the DEGs were enriched for terms related to oxidative phosphorylation and mitochondrial function pathways. Dysfunction oxidative phosphorylation metabolic pathway occurs frequently in many tumors. We validated the expression of NDUFA7, UQCRB and CCL2 using qPCR, involving in metabolism-related pathway, were significantly changed by HOXD10 overexpression in EOC. The detailed regulatory mechanism that links HOXD10 and the oxidative phosphorylation genes is not yet fully understood, our findings provide novel insight into HOXD10-mediated pathways and their effects on cancer metabolism, carcinogenesis, and the progression of EOC. Thus, the data suggest that strategies to interfere with metabolism-related pathways associated with cancer drug resistance could be considered for the treatment of ovarian tumors.

BST2 promotes gastric cancer metastasis under the regulation of HOXD9 and PABPC1.

Gastric cancer (GC) constitutes substantial cancer mortality worldwide. Several cancer types aberrantly express bone marrow stromal cell antigen 2 (BST2), yet its functional and underlying mechanisms in GC progression remain unknown. In our study, RNA sequencing data revealed that BST2 was transcriptionally activated by homeobox D9 (HOXD9). BST2 was significantly upregulated in GC tissues and promoted epithelial-mesenchymal transition and metastasis of GC. BST2 knockdown reversed HOXD9's oncogenic effect on GC metastasis. Moreover, BST2 messenger RNA stability could be enhanced by poly(A) binding protein cytoplasmic 1 (PABPC1) through the interaction between BST2 3'-UTR and PABPC1 in GC cells. PABPC1 promoted GC metastasis, which BST2 silencing attenuated in vitro and in vivo. In addition, positive correlations among HOXD9, BST2, and PABPC1 were established in clinical samples. Taken together, increased expression of BST2 induced by HOXD9 synergizing with PABPC1 promoted GC cell migration and invasion capacity.

BAP31-Mediated miR-206/133b Cluster Promotes Transendothelial Migration and Metastasis of Colorectal Cancer.

Dysregulated B cell receptor-associated protein 31 (BAP31) plays a crucial role in tumor progression. This study aimed to investigate the functions and molecular mechanism of BAP31 on the miR-206/133b cluster in colorectal cancer (CRC). qPCR was conducted to detect miRNA and mRNA levels in tissues and cells. Western blot assays were used to assess the levels of biomarkers and targets, as well as the levels of BAP31 and HOXD10. Wound healing, coculture and transwell assays were conducted to assess the transendothelial migration abilities of CRC cells. A luciferase assay was employed to assess miRNA binding effects on targets, as well as the initiating transcription effect of genomic fragments. Tumor growth and lung metastatic models were established through an in vivo animal study. BAP31 overexpression in CRC cells led to a reduction in the expression of the miR-206/133b cluster. The expression of the miR-206/133b cluster was correlated with the transendothelial migration capability of CRC cells. The miR-206/133b cluster was found to directly regulate cell division cycle 42 (CDC42) and actin-related protein 2/3 complex subunit 5 (ARPC5) in the tight junction pathway (hsa04530). Moreover, a potential transcription regulator of the miR-206/133b cluster was also found to be Homeobox D10 (HOXD10). We further elucidated the molecular mechanisms and functional mechanisms of BAP31's regulatory role in the expression levels of the miR-206/133b cluster by inhibiting HOXD10 translocation from the cytoplasm to the nucleus. In conclusion, this study provides valuable insights into how BAP31 regulates the transcription of the miR-206/133b cluster and how BAP31-related lung metastases arise in CRC.

LINC00969 inhibits proliferation with metastasis of breast cancer by regulating phosphorylation of PI3K/AKT and ILP2 expression through HOXD8.

Background: Breast cancer (BC) is a malignancy that is inadequately treated and poses a significant global health threat to females. The aberrant expression of long noncoding RNAs (lncRNAs) acts as a complex with a precise regulatory role in BC progression. LINC00969 has been linked to pyroptotic cell death and resistance to gefitinib in lung cancer cells. However, the precise function and regulatory mechanisms of LINC00969 in BC remain largely unexplored. Methods: Cell proliferation, migration, and invasion of BC cells were evaluated using CCK-8 and Transwell assays. Western blotting was employed to analyze the protein expression levels of HOXD8, ILP2, PI3K, t-AKT, and p-AKT. Results: LINC00969 was drastically reduced in BC tissues LINC00969 overexpression markedly suppressed proliferation, migration, and invasion, and blocked PI3K and p-AKT protein expression in MCF-7 cells. Activation of the PI3K/AKT pathway reversed the suppressive effect of LINC0096 overexpression on the proliferation, migration, and invasion of MCF-7 cells. Moreover, LINC00969 overexpression enhanced HOXD8 and blocked ILP2 protein expression in MCF-7 cells. In contrast, activating the PI3K/AKT pathway had no effect on HOXD8 and blocked ILP2 protein expression in MCF-7 cells overexpressing LINC00969. HOXD8 knockdown enhanced ILP2, PI3K, and p-AKT protein expression, and the proliferation, migration, and invasion of MCF-7 cells co-transfected with si-HOXD8 and ov-LINC00969. LINC00969 regulated HOXD8 via binding to miR-425-5p. Conclusion: LINC00969 inhibits the proliferation and metastasis of BC cells by regulating PI3K/AKT phosphorylation through HOXD8/ILP2.

HOXD9/miR-451a/PSMB8 axis is implicated in the regulation of cell proliferation and metastasis via PI3K/AKT signaling pathway in human anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is a deadly disease with a poor prognosis. Thus, there is a pressing need to determine the mechanism of ATC progression. The homeobox D9 (HOXD9) transcription factor has been associated with numerous malignancies but its role in ATC is unclear. In the present study, the carcinogenic potential of HOXD9 in ATC was investigated. We assessed the differential expression of HOXD9 on cell proliferation, migration, invasion, apoptosis, and epithelial-mesenchymal transition (EMT) in ATC and explored the interactions between HOXD9, microRNA-451a (miR-451a), and proteasome 20S subunit beta 8 (PSMB8). In addition, subcutaneous tumorigenesis and lung metastasis in mouse models were established to investigate the role of HOXD9 in ATC progression and metastasis in vivo. HOXD9 expression was enhanced in ATC tissues and cells. Knockdown of HOXD9 inhibited cell proliferation, migration, invasion, and EMT but increased apoptosis in ATC cells. The UCSC Genome Browser and JASPAR database identified HOXD9 as an upstream regulator of miR-451a. The direct binding of miR-451a to the untranslated region (3'-UTR) of PSMB8 was established using a luciferase experiment. Blocking or activation of PI3K by LY294002 or 740Y-P could attenuate the effect of HOXD9 interference or overexpression on ATC progression. The PI3K/AKT signaling pathway was involved in HOXD9-stimulated ATC cell proliferation and EMT. Consistent with in vitro findings, the downregulation of HOXD9 in ATC cells impeded tumor growth and lung metastasis in vivo. Our research suggests that through PI3K/AKT signaling, the HOXD9/miR-451a/PSMB8 axis may have significance in the control of cell proliferation and metastasis in ATC. Thus, HOXD9 could serve as a potential target for the diagnosis of ATC.

CircPRRC2C Promotes the Oncogenic Phenotypes of Laryngeal Squamous Cell Carcinoma Cells via MiR-136-5p/HOXD11 Axis.

The involvement of circular RNAs (circRNAs) in laryngeal squamous cell carcinoma (LSCC) carcinogenesis has gradually been proposed. Herein, we aimed to explore the function and mechanism of circPRRC2C in LSCC. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used for detecting the content of genes and proteins. In vitro experiments were conducted using 5-ethynyl-2'-deoxyuridine, colony formation, flow cytometry, and transwell assays. The binding between miR-136-5p and circPRRC2C or Homeobox D11 (HOXD11) was confirmed by using the dual-luciferase reporter assay. The murine xenograft model was established for in vivo analysis. The commercial kit was used for exosome separation. CircPRRC2C is a stable circRNA, and was highly expressed in LSCC tissues and cell lines. Functionally, circPRRC2C deficiency impaired LSCC cell proliferation, migration and invasion but induced cell apoptosis in vitro and impeded tumor growth in vivo, however, circPRRC2C overexpression showed the exact opposite effects. Mechanistically, circPRRC2C directly targeted miR-136-5p, which showed inhibitory effects on the growth and mobility of LSCC cells. Meanwhile, miR-136-5p directly targeted HOXD11, and circPRRC2C/miR-136-5p/HOXD11 formed a feedback loop in LSCC cells. Further rescue assays exhibited that circPRRC2C exerted its effects by miR-136-5p/HOXD11 axis. In addition, circPRRC2C was stably packaged into exosomes and showed potential diagnostic value for LSCC. CircPRRC2C acted as an oncogene to promote LSCC cell oncogenic phenotypes via miR-136-5p/HOXD11 axis, besides, circPRRC2C was stably packaged into exosomes, indicating the potential application of circPRRC2C-targeting agents in the treatment in LSCC.

HOXD8 suppresses renal cell carcinoma growth by upregulating SHMT1 expression.

Amplification of amino acids synthesis is reported to promote tumorigenesis. The serine/glycine biosynthesis pathway is a reversible conversion of serine and glycine catalyzed by cytoplasmic serine hydroxymethyltransferase (SHMT)1 and mitochondrial SHMT2; however, the role of SHTM1 in renal cell carcinoma (RCC) is still unclear. We found that low SHMT1 expression is correlated with poor survival of RCC patients. The in vitro study showed that overexpression of SHMT1 suppressed RCC proliferation and migration. In the mouse tumor model, SHMT1 significantly retarded RCC tumor growth. Furthermore, by gene network analysis, we found several SHMT1-related genes, among which homeobox D8 (HOXD8) was identified as the SHMT1 regulator. Knockdown of HOXD8 decreased SHMT1 expression, resulting in faster RCC growth, and rescued the SHMT1 overexpression-induced cell migration defects. Additionally, ChIP assay found the binding site of HOXD8 to SHMT1 promoter was at the -456~-254 bp region. Taken together, SHMT1 functions as a tumor suppressor in RCC. The transcription factor HOXD8 can promote SHMT1 expression and suppress RCC cell proliferation and migration, which provides new mechanisms of SHMT1 in RCC tumor growth and might be used as a potential therapeutic target candidate for clinical treatment.