Loss of HOXD10 expression induced by upregulation of miR-10b accelerates the migration and invasion activities of ovarian cancer cells

Abstract

Small and large non-coding RNAs (ncRNAs) contribute to the acquisition of aggressive tumor behavior in diverse human malignancies. Two types of ncRNAs, miRNA‑10b (miR-10b) and homemobox (HOX) transcript antisense RNA (HOTAIR), can suppress the translation of the HOXD10 gene, an mRNA encoding a transcriptional repressor that inhibits the expression of cell migration/invasion-associated genes. Using epithelial ovarian cancer cell lines and primary tumors, we investigated whether miR‑10b and/or HOTAIR can regulate the expression of HOXD10, and whether it permits gain of pro‑metastatic gene products, matrix metallopeptidase 14 (MMP14) and ras homolog family member C (RHOC). Overexpression of miR-10b induced a decrease in HOXD10 protein expression, and upregulated the migration and invasion abilities in ovarian cancer cell lines (P<0.05). In these cells, a significant increase of MMP14 and RHOC protein was observed. No significant upregulation of the HOXD10 protein was observed in cells with the treatment of HOTAIR-siRNA. Positive signals for HOXD10 and MMP14 proteins were observed in 47 (69%) and 25 (37%) of 68 patients with epithelial ovarian cancers. An inverse correlation between HOXD10 and MMP14 immunoreactivities was observed (P<0.05), and miR-10b expression was also inversely correlated with HOXD10 protein expression (P<0.05). These results suggested that downregulation of HOXD10 expression by miR-10b overexpression may induce an increase of pro-metastatic gene products, such as MMP14 and RHOC, and contribute to the acquisition of metastatic phenotypes in epithelial ovarian cancer cells.

Overexpression of miR-10b in colorectal cancer patients: Correlation with TWIST-1 and E-cadherin expression

“…17 MiR-10b has been described as an oncogenic miRNA that is overexpressed in different types of cancer and involved in tumor invasion and metastasis. [17][18][19][20][21][22][23] In this study, increased levels of miR-10b have been detected in tumor samples compared to non-tumorous adjacent mucosa. Recently, Wang et al 28 have reported that greater concentrations of miR-10b have been detected in CRC tissues compared with adjacent non-tumor tissues and normal tissues from healthy controls.…”

“…15 The transcriptional silencing of miR-10b decreases its levels and boosts the levels of HOXD10, which leads to metastasis inhibition. 16 This miRNA has been previously found to promote tumor metastasis in many malignancies, such as breast, 17 oesophageal, 18 ovarian, 19 and lung cancers. 20 While most studies report the oncogenic effect of miR-10b in gastric cancer, [21][22][23] some others show that it is downregulated mainly through CpG DNA methylation and that it may act as tumor suppressor gene in tumor tissues.…”

MicroRNA modulation combined with sunitinib as a novel therapeutic strategy for pancreatic cancer

“…47 MiR-10b was also identified as a microRNA with altered expression patterns in several cancers, being associated to suppression of HoxD10 protein synthesis and consequently allowing the expression of the RHOC gene, as a downstream signaling target, which is known to be involved in metastatic processes by inducing cell migration. 16,[48][49][50] The recognized oncomiR activity of these four microRNAs and their demonstrated deregulation in PDAC make them promising targets for new therapeutic strategies involving AMO delivery. In this regard, we further evaluated the effect of microRNA silencing on the mRNA and protein levels of the molecular targets p27 .…”

“…14,15 A few studies have identified miR-10b as a tumor promoter that determines the extent of the expression levels of the homeobox D10 (HoxD10) gene and consequently the RHOC prometastatic gene as a downstream signaling target, both of these genes being involved in metastatic processes in several types of cancers. 16,17 The increase of tumor suppressor gene expression has been a successful approach in antitumor strategies, particularly by promoting cell chemosensitivity to a broad range of therapeutic drugs used in cancer treatment. 18 For instance, downregulation of miR-21 was reported to directly reinforce susceptibility of breast cancer cells to chemotherapy.…”

Prognostic significance of microRNA-10b overexpression in breast cancer: a meta-analysis

“…Wang et al (2013) found that miR-10b was highly expressed in gastric cancer and correlated with size of tumor, Lauren classification, depth of invasion, lymph node and distant metastasis, TNM stage, and prognosis. Nakayama et al (2013) reported that miR10b overexpression may induce an increase of pro-metastatic gene products and contribute to the acquisition of metastatic phenotypes in epithelial ovarian cancer cells. Jikuzono et al (2013) demonstrated that the expression levels of miR-10b were shown to be upregulated in widely invasive follicular thyroid carcinoma that has distant metastasis and worse prognosis.…”