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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.

Breast cancer is the most frequent malignancy among females. In this study, we analyzed the expression pattern of a homeobox gene (HOXD10) in human invasive ductal breast cancer tissues and normal tissues. With the ACTB (β-actin) gene as a reference, HOXD10 was detected in 60 breast cancer tissues by using the quantitative real-time PCR (qPCR) method with the Relative Expression Software Tool (REST). We found that the HOXD10 expression level was significantly different between cancerous and normal tissues. Downregulation of the HOXD10 gene expression was examined in high-grade samples. Low-grade tissue showed no difference from the control group. HOXD10 expression was reduced in grade II breast carcinoma tissues. This data reveal that misexpression of the HOXD10 gene supports the development and involvement in breast cancer and may serve as a potential biomarker for the diagnosis of human ductal invasive breast carcinoma.

As patient survival drops precipitously from early-stage cancers to late-stage and metastatic cancers, microRNAs that promote relapse and metastasis can serve as prognostic and predictive markers as well as therapeutic targets for chemoprevention. Here we show that miR-1269a promotes colorectal cancer (CRC) metastasis and forms a positive feedback loop with TGF-β signalling. miR-1269a is upregulated in late-stage CRCs, and long-term monitoring of 100 stage II CRC patients revealed that miR-1269a expression in their surgically removed primary tumours is strongly associated with risk of CRC relapse and metastasis. Consistent with clinical observations, miR-1269a significantly increases the ability of CRC cells to invade and metastasize in vivo. TGF-β activates miR-1269 via Sox4, while miR-1269a enhances TGF-β signalling by targeting Smad7 and HOXD10, hence forming a positive feedback loop. Our findings suggest that miR-1269a is a potential marker to inform adjuvant chemotherapy decisions for CRC patients and a potential therapeutic target to deter metastasis.

Although they were discovered only in the early 1990s, many regulatory functions of microRNAs — naturally occurring short RNA sequences — have already been reported. The latest news is that they mediate cancer spread. A microRNA that may facilitate the movement of cells from one part of the embryo to another in its normal role has been found to be highly expressed in aggressive human breast cancers and to mediate breast cancer cell migration, invasion and metastasis. MicroRNAs, naturally occurring single-stranded RNA molecules involved in gene regulation, have been implicated previously in causing cancers, but this is the first report of a link to metastasis. The functional target of the microRNA appears to be the HOXD10 gene, one of the Hox gene family involved in directing embryo development.

OBJECTIVE Hox genes encode DNA transcription regulatory proteins that contain a conserved 61 amino acid protein called the homeodomain. Although best known for their role in cellular differentiation during embryonic development, aberrant expression of these genes has been associated with hematologic and solid neoplasms. The purpose of this study was to determine the relative expression of HOXD10 in human endometrial adenocarcinomas. METHODS mRNA was isolated from 7 normal endometrial specimens and 28 endometrial adenocarcinoma specimens. cDNA was synthesized using random hexamer primers. The expression of HOXD10 relative to beta-tubulin (internal control) was assessed by densitometric comparison of co-amplified Phosphorus-32 (32P) labeled gene products separated by agarose gel electrophoresis. Direct sequencing of purified HOXD10 polymerase chain reaction product was also performed. RESULTS The sequence of the purified HOXD10 product corresponds to the known DNA sequence reported in the National Institute of Health Gene Bank. mRNA expression of HOXD10 relative to beta-tubulin is significantly lower in endometrial carcinomas than in normal endometrium. Furthermore, the ratio of HOXD10 to beta-tubulin expression varies inversely with the histologic grade of the tumor (P = .0009). CONCLUSION Cancer is a multistep process involving the aberrant expression of genes that regulate cell growth and differentiation. Human HOXD10 gene expression is altered in endometrial carcinoma and varies with the histologic grade of differentiation. This observation supports the theory that homeobox genes play a role in oncogenesis.

Glioma is the most frequent primary brain tumor. Recently, the upregulation of microRNA (miR)-23a was found to be associated with glioma, but the molecular mechanism by which miR-23a promotes glioma growth remains to be unveiled. In the present study, we found that miR-23a was significantly upregulated in glioma tissues compared to their matched adjacent tissues. miR-23a was also highly expressed in glioma cell lines SHG44, U251 and U87 cells. Moreover, we identified homeobox D10 (HOXD10) as a novel target for miR-23a. The expression of HOXD10 was significantly reduced in glioma tissues and cell lines and miR-23a negatively regulates the protein expression of HOXD10 in U251 and U87 cells. We further showed that miRNA-23a promoted U251 and U87 cell invasion, at least partially, by directly targeting HOXD10 and further modulating MMP-14. These findings suggest that miR-23a may serve as a promising therapeutic target for glioma.

MicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions, which play an important role in breast cancer. Several studies have shown that miRNAs can act either as tumor suppressors or as oncogenes, and that measurement of miRNA expression in malignancies may have diagnostic and prognostic implications. This article highlights a series of three recent studies that prove the involvement of miRNAs in breast cancer metastases. The first proves that miR-10b indirectly activates the pro-metastatic gene RHOC by suppressing HOXD10, thus leading to tumor invasion and metastasis. The second proves that miR-373 and miR-520c can also promote tumor invasion and metastasis, at least in part by regulating the gene CD44. The third identifies miR-335, miR-206, and miR-126 as suppressors of breast cancer metastasis. Loss of miR-335 leads to the activation of SOX4 and TNC (encoding tenascin C), which are responsible for the acquisition of metastatic properties. Altogether, these remarkable findings are important for our understanding of malignant transformation in the breast and may have implications for the management of patients with advanced breast cancer. The use of miRNAs as anticancer therapeutic agents is promising, and such fine molecular studies certainly help in bringing miRNAs closer to clinical practice.

Glioblastoma multiforme (GBM) is a heterogeneous disease despite its seemingly uniform pathology. Deconvolution of The Cancer Genome Atlas's GBM gene expression data has unveiled the existence of distinct gene expression signature underlying discrete GBM subtypes. Recent conflicting findings proposed that microRNA (miRNA)-10b exclusively regulates glioma growth or invasion but not both. We showed that silencing of miRNA-10b by baculoviral decoy vectors in a glioma cell line resembling the mesenchymal subtype of GBM reduces its growth, invasion and angiogenesis while promoting apoptosis in vitro. In an orthotopic human glioma mouse model, inhibition of miRNA-10b diminishes the invasiveness, angiogenicity and growth of the mesenchymal subtype-like glioma cells in the brain and significantly prolonged survival of glioma-bearing mice. We demonstrated that the pleiotropic nature of miRNA-10b was due to its suppression of multiple tumor suppressors, including TP53, FOXO3, CYLD, PAX6, PTCH1, HOXD10 and NOTCH1. In particular, siRNA-mediated knockdown experiments identified TP53, PAX6, NOTCH1 and HOXD10 as invasion regulatory genes in our mesenchymal subtype-like glioma cells. By interrogating the REMBRANDT, we noted that dysregulation of many direct targets of miRNA-10b was associated with significantly poorer patient survival. Thus, our study uncovers a novel role for miRNA-10b in regulating angiogenesis and suggests that miRNA-10b may be a pleiotropic regulator of gliomagenesis.