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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: One of the important reasons for the development of preeclampsia (PE) is the abnormal function of trophoblast cells. Many circular RNAs (circRNAs) have been confirmed to participate in the regulation of trophoblast cell function to mediate PE progression. However, whether circ_0077109 is involved in PE progression through regulating trophoblast cell function remains unclear. Methods: Quantitative real‐time PCR was utilized for measuring the expression of circ_0077109, microRNA (miR)‐139‐5p and homeobox D10 (HOXD10). Trophoblast cell proliferation, apoptosis, invasion, and angiogenesis was assessed cell counting kit 8 assay, EdU assay, flow cytometry, transwell assay and tube formation assay. In addition, western blot analysis was used to determine protein expression. The interaction between miR‐139‐5p and circ_0077109 or HOXD10 was verified by dual‐luciferase reporter assay and RIP assay. Results: Our results pointed out that circ_0077109 was a circRNA with upregulated expression in PE patients. Overexpression of circ_0077109 suppressed trophoblast cell proliferation, invasion, and angiogenesis, while increased apoptosis. MiR‐139‐5p was found to be sponged by circ_0077109, and its mimic reversed the suppressive effect of circ_0077109 on trophoblast cell function. HOXD10 was a target of miR‐139‐5p, and its overexpression inhibited trophoblast cell proliferation, invasion, and angiogenesis. MiR‐139‐5p inhibitor could repress trophoblast cell function, while this effect could be reversed by HOXD10 knockdown. Conclusion: In summary, we confirmed that circ_0077109 inhibited trophoblast cell function through the regulation of miR‐139‐5p/HOXD10 axis, which might be a potential target for PE treatment. [ABSTRACT FROM AUTHOR]

Purpose: HOXD10 is a tumor modulator that can either be a tumor-suppressor or a tumor-promoting gene. However, the role of HOXD10 in glioblastoma multiforme (GBM) remains unclear. Methods: Immunohistochemistry (IHC) was applied to detect protein expression of HOXD10 in GBM and normal brain tissue patients. Clinicopathological characteristics with GBM were recorded, and a Kaplan–Meier curve was plotted. Additionally, the mRNA expression of HOXD10 and its effect on prognosis were analyzed using the online tool GEPIA and the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and the Gene Expression Omnibus (GEO) databases. Based on the mRNA expression of HOXD10, GBM patients from TCGA database were divided into low- and high-HOXD10 expression groups to analyze the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and construct a lncRNA-miRNA-mRNA network and a protein–protein interaction (PPI) network. Results: The mRNA expression of HOXD10 was up-regulated in GBM according to GEPIA, while the protein expression of HOXD10 in GBM was down-regulated according to IHC analysis of samples from patients collected from our hospital. Correlation analysis showed that HOXD10 expression was significantly related to IDH1 status. Univariate analysis revealed that low HOXD10 expression, complete surgical resection, postoperative radiotherapy, postoperative temozolomide chemotherapy and IDH1 mutation were all beneficial prognostic factors. Further multivariate analysis revealed that only complete surgical resection and postoperative radiotherapy were independent prognostic factors. GO and KEGG enrichment analyses indicated that HOXD10 expression is mainly involved in cytokine-cytokine receptor interactions. In the ceRNA network, 89 nodes, containing 45 mRNAs, 39 miRNAs and five lncRNAs associated with prognosis were involved. The PPI network revealed a tight interaction between HOXD10 and HOXD8, HOXD9, HOXD11, HOXD13 and HOXB3. Conclusion: Based on our experimental data, although HOXD10 expression is low in GBM compared with normal brain tissue, GBM patients with high HOXD10 expression have a worse prognosis. HOXD10 may play different or even opposite roles in different stages of GBM occurrence and development. For patients with GBM, HOXD10 may be a valid predictor of prognosis. [ABSTRACT FROM AUTHOR]

Homeobox D 10 (HOXD10) is important in cell differentiation and morphogenesis and serves as a tumor suppressor gene (TSG) in a number of malignancies. The present study investigated its promoter methylation status and association with the clinicopathological features of endometrial cancer (EC), and measured HOXD10 protein expression levels. EC samples (n=62), including 50 endometroid adenocarcinoma (EA) and 12 mucinous endometrial carcinoma samples (EC) and 70 non-cancerous samples were collected. All samples were evaluated for the methylation status of several TSGs, including HOXD10, using methylation-specific PCR. HOXD10 expression level was evaluated using immunohistochemistry. 5-Aza-2-deoxycytidine treatment was performed in the EC cell line Ishikawa to observe the change in HOXD10 expression levels. HOXD10 promoter methylation was more frequent in cancer samples (P<0.001). Downregulation of HOXD10 in EC samples was confirmed at the protein level using immunohistochemistry (P<0.001) and immunohistochemical staining was negatively associated with methylation status (P<0.05). Less HOXD10 protein was expressed in MEC compared with EA samples (P<0.001). The HOXD10 promoter was hypermethylated in both EA and MEC, causing decreased HOXD10 protein expression levels in EC cells. HOXD10 expression levels were partially reversed by 5-Aza-2-deoxycytidine treatment. The results of the present study demonstrated that epigenetic silencing of HOXD10 putatively contributed to the tumorigenesis of EA. Although there was no significant difference in HOXD10 methylation between EA and MEC, HOXD10 protein expression levels differed between these two diseases, indicating that it may be a useful protein biomarker for distinguishing between these two lesions. [ABSTRACT FROM AUTHOR]

Increasing number of studies have indicated aber- aberrant microRNA (miRNA) expression could affect normal biological progress in non-small cell lung cancer (NSCLC) cells. This study was performed to evaluate the biologic functions of microRNA-224 (miR-224) in NSCLC. Real-time PCR was performed to evaluate the expression of miR-224 and Homeobox D10 (HOXD10) in NSCLC cell lines and tissues. Transwell assays were performed to investigate the function of miR-224 on NSCLC cell migration and invasion. Moreover, western blotting and luciferase assays were used to investigate HOXD10 as miR-224 downstream targets. miR-224 is increased in NSCLC metastatic tissues and cell lines. Increased miR-224 expression promoted NSCLC cell migration and invasion, while low miR-224 expression suppressed NSCLC cell migration and invasion. Furthermore, HOXD10 was targeted directly by miR-224 in NSCLC cells. Moreover, we found that HOXD10 was a functional target and influenced tumour-inductive functions of miR-224 on progression of NSCLC. These findings suggest that miR-224 may be used in the treatment of NSCLC. Targeting this novel strategy, miR-224/HOXD10 axis may be helpful as promising biomarker and therapeutic method to control NSCLC cell metastasis. [ABSTRACT FROM AUTHOR]

Homeobox D10 (HOXD10) is a transcription factor from the homeobox gene family that controls cell differentiation and morphogenesis throughout development.Due to their functional interaction, changes in HOXD10 gene expression might induce tumors. This narrative review focuses on how and why the dysregulation in the signaling pathways linked with HOXD10 contributes to the metastatic development of cancer. Organ development and tissue homeostasis need highly conserved homeotic transcription factors from homeobox (HOX) genes. Their dysregulation disrupts regulatory molecule action, causing tumors. The HOXD10 gene is upregulated in breast, gastric, hepatocellular, colorectal, bladder, cholangiocellular carcinoma and prostate cancer. Tumor signaling pathways are affected by HOXD10 gene expression changes. This study examines HOXD10-associated signaling pathway dysregulation, which may alter metastatic cancer signaling. In addition, the theoretical foundations that alter HOXD10-mediated therapeutic resistance in malignancies has been presented. New cancer therapy methods will be simpler to develop with the newly discovered knowledge. This review showed that HOXD10 may be a tumor suppressor gene and a new cancer treatment target signaling pathway. [ABSTRACT FROM AUTHOR]

Colistin sulfate (polymixin E) is an antibiotic prescribed with increasing frequency for severe Gram-negative bacterial infections. As nephrotoxicity is a common side effect, the discovery of pharmacogenomic markers associated with toxicity would benefit the utility of this drug. Our objective was to identify genetic markers of colistin cytotoxicity that were also associated with expression of key proteins using an unbiased, whole genome approach and further evaluate the functional significance in renal cell lines. To this end, we employed International HapMap lymphoblastoid cell lines (LCLs) of Yoruban ancestry with known genetic information to perform a genome-wide association study (GWAS) with cellular sensitivity to colistin. Further association studies revealed that single nucleotide polymorphisms (SNPs) associated with gene expression and protein expression were significantly enriched in SNPs associated with cytotoxicity (p ≤ 0.001 for gene and p = 0.015 for protein expression). The most highly associated SNP, chr18:3417240 (p = 6.49 x 10-8), was nominally a cis-expression quantitative trait locus (eQTL) of the gene TGIF1 (transforming growth factor β (TGFβ)-induced factor-1; p = 0.021) and was associated with expression of the protein HOXD10 (homeobox protein D10; p = 7.17 x 10-5). To demonstrate functional relevance in a murine colistin nephrotoxicity model, HOXD10 immunohistochemistry revealed upregulated protein expression independent of mRNA expression in response to colistin administration. Knockdown of TGIF1 resulted in decreased protein expression of HOXD10 and increased resistance to colistin cytotoxicity. Furthermore, knockdown of HOXD10 in renal cells also resulted in increased resistance to colistin cytotoxicity, supporting the physiological relevance of the initial genomic associations. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignant disease in women, and metastasis formed at distant anatomic sites was the major cause of cancer-related mortality. Thus, a novel therapy target and progression biomarker for breast cancer metastasis was necessary. microRNA (miR)-376b has been demonstrated to regulate angiogenesis; however, its role in cancer metastasis remains elusive. In the present study, the expression of miR-376b in normal breast tissue, JC and 4T1 cells was determined by qPCR. Furthermore, in vitro and in vivo experiments were performed to determine the effect of miR-376b on breast cancer metastasis. The direct target of miR-376b was determined by the luciferase assay and western blotting. The results indicated that silencing of miR-376b by the miR-376-mimic significantly inhibited 4T1 cell migration and invasion in vitro. Lung metastasis was also evidently decreased after silencing of miR-376b in 4T1 cells. Moreover, the luciferase assay and western blotting identified that Hoxd10 is the direct target of miR-376b during the regulation of breast cancer metastasis. To the best of our knowledge, the present study was the first to demonstrate the promoting breast cancer metastasis role of miR-376b by directly targeting Hoxd10. Therefore, it would be a novel therapy target and prognostic biomarker for breast cancer. [ABSTRACT FROM AUTHOR]

Lymphangiogenesis plays a crucial role during development, in cancer metastasis and in inflammation. Activation of VEGFR-3 (also known as FLT4) by VEGF-C is one of the main drivers of lymphangiogenesis, but the transcriptional events downstream of VEGFR-3 activation are largely unknown. Recently, we identified a wave of immediate early transcription factors that are upregulated in human lymphatic endothelial cells (LECs) within the first 30 to 80 min after VEGFR-3 activation. Expression of these transcription factors must be regulated by additional pre-existing transcription factors that are rapidly activated by VEGFR-3 signaling. Using transcription factor activity analysis, we identified the homeobox transcription factor HOXD10 to be specifically activated at early time points after VEGFR-3 stimulation, and to regulate expression of immediate early transcription factors, including NR4A1. Gain- and loss-of-function studies revealed that HOXD10 is involved in LECs migration and formation of cord-like structures. Furthermore, HOXD10 regulates expression of VE-cadherin, claudin-5 and NOS3 (also known as e-NOS), and promotes lymphatic endothelial permeability. Taken together, these results reveal an important and unanticipated role of HOXD10 in the regulation of VEGFR-3 signaling in lymphatic endothelial cells, and in the control of lymphangiogenesis and permeability. [ABSTRACT FROM AUTHOR]

Background: This study aims to investigate the effect of miR-10b overexpression on cancer cell proliferation, migration, invasion, and Hoxd10 expression. Methods: The effect of miR-10b on proliferation, migration, and invasion of MKN-28, BGC-823, and SGC-7901 cells and the expression of Hoxd10 protein in SGC-7901 and BGC-823 cells were detected following transfection of miR-10b inhibitor or Negative Control B. Expression of Hoxd10 protein in 436 paraffin-embedded cancer tissues was also investigated. Results: miR-10b was significantly upregulated in AGS, MKN-28, BGC-823, HCG-27, SGC-7901, and MKN-45 cell lines, miR-10b inhibitor significantly inhibited proliferation and migration of MKN-45, BGC-823 and SGC-7901 cells 48 h after transfection, while Hoxd10 protein in these cells lines had increased 72 h after transfection. Hoxd10 was highly expressed in gastric cancer and correlated with size of tumor, Lauren classification, depth of invasion, lymph node and distant metastasis, Tumor-Node-Metastasis (TNM) stage, and prognosis. Conclusions: miR-10b promotes migration and invasion through Hoxd10 in human gastric cancer cell lines and may play an important role in tumorigenesis, progression, and prognosis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the expression of hoxd10 and p53 protein in hepatocellular carcinoma,and then to determine the clinicopathological significance. Methods: Determine the expression of HOXD10 and p53 protein in the 62 cases of HCC and adjacent liver tissues, 20 cases of benign liver tissues by immunohistochemistry method and analyze the relationship between the HOXD10, P53 protein expression in HCC tissue and clinicopathological features of HCC patients. Results: HOXD10 protein expression in poorly differentiated HCC tissues was significantly lower than in differentiated, highly-differentiated HCC, paraneoplastic and benign liver tissue(P<0.05), But the expression of P53 in poorly differentiated HCC tissues was significantly higher than in well-differentiated HCC tissue(P<0.05), HOXD10 protein expression is negative related to the vascular invasion in HCC tissue(r=-0.299, P=0.026).No correlations were found between HOXD10 and P53 protein and other clinical pathological factors,including sex, age, tumor size,multiple nodules, surrounding liver cirrhosis(P>0.05). Conclusion: Low expression of HOXD10 and P53 high levels is closely related to poorly differentiated HCC. It may be used as a reference index to treatment and prognosis predict. [ABSTRACT FROM AUTHOR]

Background and Aim Micro RNAs (mi RNAs) are small noncoding RNA molecules that control target gene expression and are implicated in the regulation of diverse cellular pathways. In our previous research, we have demonstrated that mi R-224 was overexpressed in liver cancer cells and tissues, which was an important factor in the regulation of cell migration and invasion. This study aimed to further explore the regulatory mechanism of mi R-224 in the migration and invasion in liver cancer cells. Methods A luciferase reporter assay was used to confirm that the HOXD10 gene was a direct target of mi R-224. Quantitative reverse transcriptase-polymerase chain reaction, Western blotting, Transwell migration, and Matrigel invasion assays were performed to clarify the molecular mechanism of mi R-224 in the regulation of cell migration and invasion in human hepatocellular carcinoma ( HCC). Results (i) The expression of mi R-224 was strongly upregulated in MHHC97 H and MHCC97 L cells, and its expression level was significantly associated with cell invasive potential. (ii) The HOXD10 gene was confirmed to be a direct target of mi R-224. Compared with normal liver tissues and cells, HOXD10 had lower expression in HCC tissues and cells and inversely regulated HCC cell invasion. (iii) mi R-224 promoted expression of the tumor invasion-associated proteins p- PAK4 and MMP-9 by directly targeting HOXD10. Conclusion Our findings suggest a previously undescribed regulatory pathway in which the mi R-224/ HOXD10/p- PAK4/ MMP-9 signaling pathway contributes to the regulation of cell migration and invasion and provides a new biotarget for HCC treatment. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Are other HOX genes, in addition to HOXA10, involved in endometrial receptivity? SUMMARY ANSWER The highly expressed HOXA9, HOXA11 and HOXD10 genes also appear to be involved in endometrial receptivity. WHAT IS KNOWN ALREADY Within the HOX family of homeobox transcription factor genes are the leading candidates for the regulation of embryonic implantation. A crucial role of HOXA10 in endometrial receptivity has been well established. STUDY DESIGN, SIZE, DURATION To identify HOX candidate genes, we performed data mining on all 39 human HOX genes in the ‘Human body index’ gene expression database of normal human tissue. The temporal and spatial expression pattern of four highly expressed HOX genes in the human endometrium was determined. To further investigate the function of these Hox genes, we used a robust in vivo mouse model in which we blocked maternal Hox gene expression. PARTICIPANTS/MATERIALS, SETTING AND METHODS Analysis of a gene expression profile set in the public domain consisting of 504 samples representing 95 different normal human tissues, showed that in addition to HOXA10, also HOXA9, HOXA11, HOXB6 and HOXD10 mRNA showed increased expression in the human endometrium (16 samples). The temporal and spatial expression pattern of these four HOX genes throughout the menstrual cycle was determined in the endometrium from 27 female patients eligible for IVF-embryo transfer with a normal cycle by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry. The role of maternal Hoxa9, Hoxa11 and Hoxd10 was assessed in a mouse implantation model by expression knockdown using RNA interference. Forty mice were transfected with Hoxa9-, Hoxa11- or Hoxd10-specific small hairpin RNA (shRNA) constructs or a vector control by injection into the uterine horn at Day 2 after vaginal plug detection (Day 1) (160 mice in total). The effects were examined by qRT-PCR and western blot at Day 4 and litter sizes counted at Day 9 of pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE HOXA10, HOXA9, HOXA11 and HOXD10 all showed increased expression during the mid-secretory phase of the menstrual cycle (P < 0.01). Knockdown of Hoxa9, Hoxa11 and Hoxd10 in the murine uterus resulted in significantly reduced average implantation rates (P < 0.01) and, with regard to four Hox target genes, also correlated with a significantly increased empty spiracles homolog 2 (Emx2) and insulin-like growth factor binding protein-1 (Igfbp1), and decreased integrin β3 (Itgb3) and leukemia inhibitory factor (Lif), expression (P < 0.01). LIMITATIONS, REASONS FOR CAUTION Menstrual cycle stage was not confirmed by serum hormone analysis. We verified the absence of significant differences in stage-specific expression of the reference genes used in our study (ACTB/Actb and GAPDH/Gapdh) and therefore possible limitations of this approach were minimized. In addition, the translatability of our data from a mouse model to patients needs to be investigated further. WIDER IMPLICATIONS OF THE FINDINGS We provide evidence that three other HOX genes in addition to HOXA10 are involved in endometrial receptivity, and that part of their function is asserted through several known HOX target genes, suggesting the presence of a central HOX signal transduction pathway. STUDY FUNDING/COMPETING INTEREST(S) This project was funded by the National Natural Science Foundation of China. The authors declare no conflict of interest. [ABSTRACT FROM AUTHOR]

Abstract: Renal malformations are commonly found among patients carrying a 22q11 deletion which renders loss of Tbx1 gene, an important transcriptional factor implicated in a number of developmental processes. Smad1 is known to interact with Tbx1, but the exact mechanism remains unknown. In this study, we have measured the expression of Tbx1 in both murine and human tissues using RT-PCR, and analyzed its protein product and protein-protein interactions with Western blotting and immunoprecipitation assays. Precipitated proteins were verified with mass spectrometry. As discovered, Tbx1 binds with Hoxd10. Tbx1 and Hoxd10 genes also have similar expression profiles during murine kidney development. Based on homology between mouse and human, we hypothesized that such interaction also exists in human. Through a RNA interference experiment using a human embryonic kidney HEK293 cell line, we demonstrated that TBX1 can alter TGF-β/BMP, an important signaling pathway, through interacting with HOXD10. Above findings may shed light on the mechanism of TBX1 mutations leading to renal malformations found in patients carrying a 22q11 deletion. [Copyright &y& Elsevier]

Abstract: MicroRNAs are small endogenous noncoding RNAs, which modulate target gene expression by binding with target mRNA sequences in the 3′untranslated region (UTR) with an imperfect complementarity that inhibits the mRNA translation. Many microRNAs have been reported to function as tumor oncogenes or anti-oncogenes. Recently, more and more microRNAs have been reported to contribute to a tumor''s invasive potential. Here, we show that microRNA-10b (miR-10b) was over-expressed in glioma samples and directly associated with the glioma''s pathological grade and malignancy. We also found that miR-10b induced glioma cell invasion by modulating tumor invasion factors MMP-14 and uPAR expression via the direct target HOXD10. The miR-10b/HOXD10/MMP-14/uPAR signaling pathway might contribute to the invasion of glioma. Accordingly, glioma cells lost their invasive ability when treated with specific antisense oligonucleotides (miR-10b inhibitors), suggesting that miR-10b could be used as a new bio-target to cure glioma. [Copyright &y& Elsevier]

Abstract: Prolactinoma is one of the most common types of pituitary adenoma. It has been reported that a variety of growth factors and cytokines regulating cell growth and angiogenesis play an important role in the growth of prolactinoma. HoxD10 has been shown to impair endothelial cell migration, block angiogenesis, and maintain a differentiated phenotype of cells. We investigated whether HoxD10 gene delivery could inhibit the growth of prolactinoma. Rat GH4 lactotrope tumor cells were infected with adenovirus/adeno-associated virus (Ad/AAV) hybrid vectors carrying the mouse HoxD10 gene (Hyb-HoxD10) or the β-galactosidase gene (Hyb-Gal). Hyb-HoxD10 expression inhibited GH4 cell proliferation in vitro. The expression of FGF-2 and cyclin D2 was inhibited in GH4 cells infected with Hyb-HoxD10. GH4 cells transduced with Hyb-HoxD10 did not form tumors in nude mice. These results indicate that the delivery of HoxD10 could potentially inhibit the growth of PRL-secreting tumors. This approach may be a useful tool for targeted therapy of prolactinoma and other neoplasms. [Copyright &y& Elsevier]

Background: To examine the influence of HOXD10 on the metabolism and growth of colon carcinoma cells by suppressing the RHOC/AKT/MAPK pathway. Methods: Thirty-seven paired colon cancer and its adjacent samples from The Cancer Genome Atlas (TCGA) were analyzed. Chip Analysis Methylation Pipeline (ChAMP) analysis was employed for differential methylated points (DMPs) and the differential methylation regions (DMRs) screening. The HOXD10 mRNA expression and DNA methylation levels were detected by RT-PCR. The Cell proliferation, migration, invasion and apoptosis were respectively measured by MTT assay, transwell assay, wound healing assay and flow cytometry assay in carcinoma cell lines after treated with 5-aza-2′-deoxycytidine (5-Aza-dC) or transfected with HOXD10-expressing plasmid. The expression of HOXD10 and RHOC was revealed by immunohistochemistry in disparate differentiation colon carcinoma tissues, and the dephosphorylation of AKT and MAPK pathways were detected by RT-PCR and western blot. Results: The bioinformatics analysis demonstrated that HOXD10 was hypermethylated and low-expressed in colorectal cancer tissues. The detection of RT-PCR indicated the similar results in colorectal cancer cell lines and tissues. The induction of demethylation was recovered by treatment with 5-Aza-dC and the HOXD10 in colorectal cancer cell lines was re-expressed by transfection with a HOXD10 expression vector. The demethylation or overexpression of HOXD10 suppressed proliferation, migration, invasion and promoted apoptosis in colorectal cancer cells. HXOD10 suppressed the tumor growth and detected an opposite trend of protein RHOC. AKT and MAPK pathways were notably inactivated after the dephosphorylation due to the overexpression of HOXD10. Conclusions: HOXD10 was suppressed in colon adenocarcinoma cells, which down-regulated RHOC/AKT/MAPK pathway to enhance colon cancer cells apoptosis and constrain the proliferation, migration and invasion. [ABSTRACT FROM AUTHOR]

Objective: We had previously reported a mouse line carrying the Atypical female courtship (HoxDAfc) allele, where an ectopic accumulation of Hoxd10 transcripts was observed in a sparse population of cells in the adult isocortex, as a result of a partial deletion of the HoxD gene cluster. Female mice carrying this allele displayed an exacerbated paracopulatory behavior, culminating in a severe mutilation of the studs’ external genitals. To unequivocally demonstrate that this intriguing phenotype was indeed caused by an illegitimate function of the HOXD10 protein, we use CRISPR/Cas9 technology to induce a microdeletion into the homeobox of the Hoxd10 gene in cis with the HoxDAfc allele. Results: Females carrying this novel HoxDDel(1–9)d10hd allele no longer mutilate males. We conclude that a brain malfunction leading to a severe pathological behavior can be caused by the mere binding to DNA of a transcription factor expressed ectopically. We also show that in HoxDAfc mice, Hoxd10 was expressed in cells containing glutamate decarboxylase (Gad1) and Cholecystokinin (Cck) transcripts, corroborating our proposal that a small fraction of GABAergic neurons in adult hippocampus may participate to some aspects of female courtship. [ABSTRACT FROM AUTHOR]