Melanoma is derived from melanocytes and accounts for ~80% of skin cancer-associated fatalities worldwide. The dysregulation of microRNAs (miRNAs/miRs) is involved in the development and progression of melanoma. Therefore, miRNAs may be novel diagnostic or prognostic biomarkers and promising therapeutic targets in the treatment of patients with melanoma. miR‑675 is differentially expressed in several types of human cancer and has important roles in the pathogenesis of several diseases. However, the expression levels and the biological roles of miR‑675 in melanoma remain unclear. Therefore, the present study aimed to assess the expression of miR‑675 in melanoma, explore the effects of miR‑675 on melanoma cells and investigate the underlying molecular mechanisms that may be involved in the actions of miR‑675. The present study indicated that miR‑675 expression was downregulated in melanoma tissues and cell lines. Functional assays demonstrated that the upregulation of miR‑675 impaired cell proliferation and invasion in melanoma. Bioinformatics analysis, luciferase reporter assay, reverse transcription‑quantitative polymerase chain reaction and western blot analysis demonstrated that metadherin (MTDH) was a direct target of miR‑675 in melanoma. The MTDH levels were upregulated in melanoma tissues and inversely correlated with the miR‑675 expression. Furthermore, restored MTDH expression rescued the inhibition effects in melanoma cells caused by miR‑675 overexpression. Thus, miR‑675 may be a potential therapeutic target for melanoma.

Recent studies have suggested that miR-30e-5p is dysregulated in several human carcinomas; however, the mechanism of miR-30e-5p in bladder cancer (BCa) remains unknown. Here, we confirmed that the expression of miR-30e-5p was decreased in human BCa specimens and cell lines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Upregulation of miR-30e-5p decreased the proliferation and migration in T24 and UM-UC-3 cells. Metadherin (MTDH) was a potential target for miR-30e-5p through bioinformatics analysis. Dual-luciferase assays were conducted to validate the interaction between miR-30e-5p and MTDH, which demonstrates that the relative luciferase activity was significantly downregulated after transfected miR-30e-5p mimic compared with control mimic in 293T cells. We also detected that whether silencing of MTDH by using small interfering(si)-MTDH matched effects caused by miR-30e-5p overexpression in BCa cells lines by Cell Counting Kit-8 (CCK-8), colony formation, and transwell assay, and we found the effects of silencing of MTDH same as miR-30e-5p overexpression. Furthermore, we verified that the restoration of MTDH in miR-30e-5p-overexpressed BCa cells rescued the inhibitory effects of miR-30e-5p. In conclusion, these results demonstrated that miR-30e-5p may inhibit BCa cells growth and invasiveness by targeting MTDH and may be a promising therapeutic agent for treating clinical BCa patients.

Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein. We had reported that CPEB3 is involved in hepatocellular carcinoma (HCC) progression. However, the underlying mechanisms of CPEB3 in HCC remain unclear. In this study, we firstly performed RNA immunoprecipitation to uncover the transcriptome-wide CPEB3-bound mRNAs (CPEB3 binder) in HCC. Bioinformatic analysis indicates that CPEB3 binders are closely related to cancer progression, especially HCC metastasis. Further studies confirmed that metadherin (MTDH) is a direct target of CPEB3. CPEB3 can suppress the translation of MTDH mRNA in vivo and in vitro. Besides, luciferase assay demonstrated that CPEB3 interacted with 3'-untranslated region of MTDH mRNA and inhibited its translation. Subsequently, CPEB3 inhibited the epithelial-mesenchymal transition and metastasis of HCC cells through post-transcriptional regulation of MTDH. In addition, cpeb3 knockout mice are more susceptible to carcinogen-induced hepatocarcinogenesis and subsequent lung metastasis. Our results also indicated that CPEB3 was a good prognosis marker, which is downregulated in HCC tissue. In conclusion, our results demonstrated that CPEB3 played an important role in HCC progression and targeting CPEB3-mediated mRNA translation might be a favorable therapeutic approach.

Prostate cancer is the second most common cancer in men worldwide. This study focused to clarify the roles of Metadherin (MTDH) and miR-342-3p in prostate cancer. We identified that MTDH was up-regulated and miR-342-3p was down-regulated in the prostate tissues, and there is an inverse correlation between MTDH and miR-342-3p. Functional studies revealed that miR-342-3p directly targets MTDH via binding to the 3' untranslated regions (UTRs) in the prostate cancer cells. Moreover, we also found MTDH overexpression in DU145 and PC3 cells inhibited apoptosis. Subsequently, miR-342-3p has been revealed to reverse the MTDH effect on the cellular apoptosis in the further studies. Our results indicate that MTDH repress apoptosis of prostate cancer in vitro and provides a new strategy for human prostate cancer therapy in the future.

Metadherin (MTDH), also known as astrocyte-elevated gene-1, was first cloned in 2002 and has been confirmed as an oncogene in numerous types of cancer by previous studies. Overexpression of MTDH has been observed in multiple types of cancer, including breast, esophageal, prostate, cervical and non-small-cell lung cancer, as well as neuroblastoma and hepatocellular carcinoma. However, at present, few investigations into MTDH‑associated prostate cancer have been performed. A previous study suggested that MTDH was expressed at higher levels in prostate cancer samples, compared with those of benign prostatic hyperplasia. The present study aimed to elucidate the effects of MTDH as an oncogene associated with the biological behavior of prostate cancer cells and chemotherapy-sensitivity to cisplatin in vitro. It was demonstrated that the inhibition of MTDH expression promoted cell apoptosis, reduced cell viability and weakened the invasive ability of prostate cancer cells. In addition, the suppression of MTDH expression increased cell sensitivity to cisplatin. Furthermore, it was demonstrated that MTDH‑associated phosphoinositide 3-kinase/Akt signaling pathways may be involved in mediating the biological behavior of prostate cancer.

Ovarian cancer has a high mortality rate among women worldwide. Radiotherapy is considered an effective method of ovarian cancer treatment, however, radioresistance presents a challenge. It is necessary to develop techniques that can increase radiosensitivity in ovarian cancer, and gene therapy is a promising option. The aim of the present study was to investigate the effects of metadherin (MTDH) silencing on the radiosensitivity of ovarian cancer. Ovarian cancer tissues (n=273) and normal ovarian tissues (n=277) were used, as were SKOV3 ovarian cancer cells and the immortalized human ovarian epidermal HOSEpiC cell line. MTT, Transwell and wound-healing assays were performed to assess the proliferation, invasion and migration abilities of the SKOV3 cells. Colony-forming assays and flow cytometry were applied to detect the radiosensitivity and apoptosis of the SKOV3 cells. Nude mouse xenograft models were established to evaluate the effect of MTDH gene silencing on tumor growth and the efficacy of radiotherapy. Ovarian cancer, in tissues and cells, was demonstrated to have a high level of MTDH. Additionally, MTDH silencing was found to significantly inhibit proliferation, migration and invasion, and induce apoptosis in SKOV3 cells, and it was suggested that MTDH depletion significantly increased the sensitivity of the SKOV3 cells to X-ray radiation. MTDH silencing enhanced radiosensitivity and delayed tumor growth in the nude mouse xenograft model. Collectively, the results obtained in the present study suggest the potential role of MTDH silencing as a technique for ameliorating radioresistance in ovarian cancer. The present study provides a promising experimental basis for the improvement of ovarian cancer radiotherapy treatment.

Astrocyte elevated gene-1 (AEG-1), also known as MTDH (metadherin) or LYRIC, is an established oncogene. However, the physiological function of AEG-1 is not known. To address this question, we generated an AEG-1 knock-out mouse (AEG-1KO) and characterized it. Although AEG-1KO mice were viable and fertile, they were significantly leaner with prominently less body fat and lived significantly longer compared with wild type (WT). When fed a high fat and cholesterol diet (HFD), WT mice rapidly gained weight, whereas AEG-1KO mice did not gain weight at all. This phenotype of AEG-1KO mice is due to decreased fat absorption from the intestines, not because of decreased fat synthesis or increased fat consumption. AEG-1 interacts with retinoid X receptor (RXR) and inhibits RXR function. In enterocytes of AEG-1KO mice, we observed increased activity of RXR heterodimer partners, liver X receptor and peroxisome proliferator-activated receptor-α, key inhibitors of intestinal fat absorption. Inhibition of fat absorption in AEG-1KO mice was further augmented when fed an HFD providing ligands to liver X receptor and peroxisome proliferator-activated receptor-α. Our studies reveal a novel role of AEG-1 in regulating nuclear receptors controlling lipid metabolism. AEG-1 may significantly modulate the effects of HFD and thereby function as a unique determinant of obesity.

Since its original discovery in 2002, AEG-1/MTDH/LYRIC has emerged as a primary regulator of several diseases including cancer, inflammatory diseases, and neurodegenerative diseases. AEG-1/MTDH/LYRIC has emerged as a key contributory molecule in almost every aspect of cancer progression, including uncontrolled cell growth, evasion of apoptosis, increased cell migration and invasion, angiogenesis, chemoresistance, and metastasis. Additionally, recent studies highlight a seminal role of AEG-1/MTDH/LYRIC in neurodegenerative diseases and obesity. By interacting with multiple protein partners, AEG-1/MTDH/LYRIC plays multifaceted roles in the pathogenesis of a wide variety of diseases. This review discusses the current state of understanding of AEG-1/MTDH/LYRIC regulation and function in cancer and other diseases with a focus on its association/interaction with several pivotal protein partners.

Prognosis identifies the seriousness and the chances of survival of a cancer patient. However, it remains a challenge to identify the key cancer genes in prognostic studies. In this study, we collected 2064 genes that were related to prognostic studies by using gene expression measurements curated from published literatures. Among them, 1820 genes were associated with copy number variations (CNVs). The further functional enrichment on 889 genes with frequent copy number gains (CNGs) revealed that these genes were significantly associated with cancer pathways including regulation of cell cycle, cell differentiation and mitogen-activated protein kinase (MAPK) cascade. We further conducted integrative analyses of CNV and their target genes expression using the data from matched tumour samples of The Cancer Genome Atlas (TCGA). Ultimately, 95 key prognosis-related genes were extracted, with concordant CNG events and increased up-regulation in at least 300 tumour samples. These genes, and the number of samples in which they were found, included: ACTL6A (399), ATP6V1C1 (425), EBAG9 (412), FADD (308), MTDH (377), and SENP5 (304). This study provides the first observation of CNV in prognosis-related genes across pan-cancer. The systematic concordance between CNG and up-regulation of gene expression in these novel prognosis-related genes may indicate their prognostic significance.

Migraine is a common brain disorder with a large genetic component. Of the two main migraine types, migraine with aura and migraine without aura, the genetic underpinning in the former is least understood. Given the evidence from epidemiological studies in cohorts and families that the genetic contribution is highest in migraine with aura, this seems paradoxical. Various genetic approaches have been applied to identify genetic factors that confer risk for migraine. Initially, so-called candidate gene associations studies (CGAS) have been performed that test DNA variants in genes prioritized based on presumed a priori knowledge of migraine pathophysiology. More recently, genome-wide association studies (GWAS) tested variants in any gene in an hypothesis-free manner. Whereas GWAS in migraine without aura, or the more general diagnosis migraine have already identified dozens of gene variants, the specific hunt for gene variants in migraine with aura has been disappointing. The only GWAS specifically investigating migraine with aura yielded only one single associated single nucleotide polymorphism (SNP), near MTDH and PGCP, with genome-wide significance. However, interrogation of all genotyped SNPs, so beyond this one significant hit, was more successful and led to the notion that migraine with aura and migraine without aura are genetically more alike than different. Until now, most relevant genetic discoveries related to migraine with aura came from investigating monogenetic syndromes with migraine aura as a prominent phenotype (i.e. FHM, CADASIL and FASPS). This review will highlight the genetic findings relevant to migraine with aura.

Keywords: Aura; Complex; GWAS; Genetics; Migraine; Monogenic; Mutation; Variant.

Metadherin (MTDH) is a protein that is also named astrocyte elevated gene-1, and is highly expressed in a number of different tumor tissues. Although the expression of MTDH is associated with tumor invasion and recurrence, the expression of this protein in perihilar cholangiocarcinoma (PCCA) and its clinical use have not yet been investigated. In the present study, the expression of MTDH in patients with PCCA was investigated in order to determine its clinicopathological use. An immunohistochemical method was used to detect MTDH expression and the epithelial-mesenchymal transition markers E-cadherin and vimentin in 66 cases of PCCA. In addition to the expression of MTDH, the clinical and pathological data and the postoperative outcomes were analyzed. The MTDH positive expression rate was 48.5% (32/66) in PCCA. A significantly higher MTDH expression level was identified in the poor tumor differentiation group compared with the well differentiation group (P=0.007). In the positive lymph node metastasis group, a significantly higher MTDH expression level was revealed compared with the negative lymph node metastasis group (P=0.023). No association was noted with regard to the expression of MTDH and the variables age, sex, tumor diameter, tumor grade and tumor classification stage. Positive MTDH expression was significantly associated with high vimentin expression (P=0.037) compared with negative vimentin expression and inversely associated with positive E-cadherin expression compared with negative E-cadherin expression (P=0.030). Survival analysis suggested that the high MTDH expression group was associated with a worse overall survival (OS) rate and recurrence free survival (RFS) rate compared with the low MTDH expression group (P<0.001 and P=0.01, respectively). Cox regression analysis indicated that the Tumor-Node-Metastasis, surgery margin and high MTDH expression were independent OS and RFS factors for PCCA. MTDH expression may serve an important function in PCCA tumor growth and metastasis. Targeting MTDH may have important therapeutic applications for patients with PCCA.

BACKGROUND Breast cancer is a common malignant tumor worldwide. Despite the huge advances in modern medicine, many patients still face a high risk of recrudescent and metastatic breast cancer. Berberine was widely implemented in clinic treatment of breast cancer. This study was performed to contribute to a better understanding on the mechanisms underlying berberine affecting breast cancer. MATERIAL AND METHODS We mined survival data of metadherin (MTDH) in breast cancer patients through Kaplan-Meier Plotter and analyzed the transcriptional and posttranscriptional expression profile of MTDH in several breast cancer cell lines. The cell viability and MTDH mRNA level were detected under the si-MTDH vector and different concentrations of berberine. The MTDH-expression vector was transfected into MCF-7 and MDA-MB-231 cells, and the changes of cell viability and apoptosis were determined after berberine (50 μM) treatment. RESULTS High MTDH expression was related to worse relapse-free survival (RFS) of breast cancer (P-value=6.2e-08). High-expressed MTDH is common in breast cancer cells, compared with that in normal breast cells (P<0.01). MTDH knockout could inhibit the viabilities of MCF-7 and MDA-MA-231 cells (P<0.01). When the concentration was higher than 10 μM, the suppressive effects of berberine on viability and MTDH reached significant level. As MTDH expression increased, the enhanced apoptosis rates of breast cancer cells by berberine were remarkably inhibited. CONCLUSIONS High-expressed MTDH was helpful to cell proliferation and survival in breast cancer. The anti-cancer ability of berberine in breast cancer may be partially dependent on the regulation of MTDH.

Epithelial-mesenchymal transition (EMT) leads to tumor dissemination and metastasis. Metadherin (MTDH) is an oncogene that plays an important role in metastasis regulation. This study tries to investigate the effect of MTDH gene up-regulation on the activation of EMT in colorectal cancer (CRC) cells and identify the role of NF-κB p65. The CaCO2 cells were divided into three groups: one control group of cultured CaCO2 cells (C1), and two groups of CaCO2 cells co-transfected using human MTDH expression plasmid with either siRNA targeting human NF-κB p65 or its negative control (C2 and C3 respectively). The gene modification was confirmed by qPCR and the effect of gene modification on CRC aggravation was studied. MTDH up-regulation significantly promoted CRC cell proliferation, activated anaerobic respiration (glucose consumption and lactate production), and increased gene expression of multidrug resistance gene (MDR1), Snail transcription factor and NF-κB p65, but decreased the gene expression of E-cadherin. Moreover, MTDH up-regulation led to a significant increase in the acquisition of surface markers of CRC stem cells. Interference with NF-κB p65 gene expression reversed the action of MTDH gene up-regulation on MDR1 and E-cadherin gene expression and anaerobic respiration. Moreover, NF-κB p65 interference significantly decreased MTDH-induced cell proliferation and acquisition of surface markers of CRC stem cells but didn't affect the Snail transcription factor. MTDH-dependent EMT in CRC is activated via NF-κB p65 and is mediated by up-regulation of Snail. These results identify a pathway by which MTDH regulates NF-κB p65 induced EMT during CRC cell metastasis.

Studies have rarely been conducted on the role of miRNAs in prostate cancer (PCa) cell progression by directly targeting MTDH, at least to the best of our knowledge. Thus, the present study aimed to identify miRNAs closely related with metadherin (MTDH) and to determine their roles in PCa. For this purpose, the expression levels of MTDH in PCa tissues and cell lines were examined by RT‑qPCR, immunohistochemistry and western blot analysis. By cell transfection, MTDH was either overexpressed in the normal prostate epithelial cell lines or silenced in tumor cell lines to determine cell viability, invasion and migration. Bioinformatics analysis, RT‑qPCR, western blot analysis, dual‑luciferase reporter assay and MTT assay were performed to identify direct the target of MTDH and to examine tumor cell viability. Rescue experiments using the PC‑3 and LNCaP cells were carried out by MTT assay, scratch wound assay, Transwell assay, RT‑qPCR and western blot analysis. Experiments were also conducted using 46 PCa human cancer and adjacent tissues, as wells as on 501 cases of PCa from the TCGA database. It was confirmed that the overexpression of MTDH was associated with a poor prognosis of patients. The overexpression of MTDH was found to promote the viability, invasion and migration of PCa cells. miR‑145‑5p and miR‑145‑3p identified from 16 miRNAs were found to be closely related to PCa and to be the targets of MTDH. Both these miRNAs were found to significantly suppress the growth and metastasis of PCa cells by negatively regulating the expression of MTDH. On the whole, the findings of this study demonstrate that MTDH functions as an oncogene in PCa and the inhibition of MTDH by miR‑145‑5p or miR‑145‑3p suppressed the growth and metastasis of PCa cells. The miR‑145‑5p/MTDH and miR‑145‑3p/MTDH pathways may thus become novel treatment targets for PCa.

Artificially designed miRNAs mimics and inhibitors that specifically target known oncogenes have attracted significant research attention. Herein, we aimed to explore whether MIR-375, MIR-145, and MIR-224 are involved in induction of apoptosis of CRC cells by regulating apoptosis-mediating genes MTDH, MAP3K1, PDK1, BAX, and BCL-XL. MTT assay was used to assess cell growth. Apoptosis was determined in terms of caspase activity measurement and phosphatidylserine detection using annexin V staining by flow cytometry. Quantitative real time PCR, Western blotting, and luciferase reporter assay were carried out to validate genes regulation and targeting by miRNAs. We found that ectopic expression of MIR-375 and MIR-145, and inhibition of MIR-224 can decrease cell growth and induce cell ability to undergo early apoptosis. At mRNA level, transfected cells displayed down-regulation of MTDH, PDK1 and BCL-XL, while BAX and MAP3K1 were up-regulated. Protein expression of MTDH was decreased in cells transfected with MIR-145 mimic and MIR-224 inhibitor but remained unchanged in MIR-375 mimic-transfected cells. Furthermore, MAP3K1 protein expression exibited a decreased level after MIR-375 transient expression with no significant change after MIR-145 mimic or MIR-224 inhibitor transfection. Luciferase reporter assay revealed that MIR-375 and MIR-145 can bind to 3'UTR of MTDH, supporting that MTDH is directly targeted by both miRNAs. Similarly, MAP3K1 was found to be directly regulated by MIR-375. The study concluded that the expression modulation of tumor suppressors MIR-375 and MIR-145, and oncomiR MIR-224 have the ability to induce apoptosis of CRC cells through regulation of apoptosis mediating genes MTDH, MAP3K1, PDK1, BCL-XL and BAX.

RNA-binding factor 1 (AUF1) was found to be up-regulated in numerous tumors compared with untransformed tissues. Furthermore, it has been identified to regulate mRNAs en masse in hepatocellular carcinoma (HCC). Metadherin (MTDH) as a novel oncogene also promotes tumor progression and metastasis in HCC. Our study aimed to investigate the correlation between AUF1 and MTDH expressions by immunochemistry in 146 HCC patients from Heilongjiang region. AUF1 expression in HCC tumors was higher than that in the matched normal liver tissues. Particularly, AUF1 overexpression was closely associated with tumor size (P < 0.022), TNM stage (P < 0.003), hepatitis B surface antigen status, and AFP serum levels (P < 0.05). Furthermore, AUF1 overexpression led to poor outcome during 5-year follow-up (P < 0.001). Additionally, AUF1 and MTDH expressions were correlated with each other. Our findings suggest that the AUF1 gene may play an important role in HCC progression and be a novel biomarker in the future.

OBJECTIVE

To study the expression and clinical significance of MTDH and VEGF in triple-negative breast cancer (TNBC).

METHODS

Tissue samples of 168 breast cancers (including 112 TNBC tissue and 56 non-TNBC tissue), 10 breast fibroadenomas and 15 normal breast tissues were collected. Postoperative specimens were examined by immunohistochemistry for MTDH and VEGF expression. The correlation between the expression of MTDH and VEGF and clinicopathological features was analyzed.

RESULTS

MTDH and VEGF were expressed in 57.1% and 49.4% of breast cancer patients, 64.3% and 56.3% in TNBC patients, respectively, significantly higher than that in the non-TNBC tissues, breast fibroadenomas and normal breast tissues (P<0.05 for all). Statistically significant correlation was found between the MTDH and VEGF expressions (r=0.356, P<0.001). Moreover, MTDH expression was correlated with tumor size, BMI index, lymph node metastasis, pathological stage, recurrence and metastasis, and the expression of p53 and Ki-67 proteins (P<0.05 for all). The VEGF protein expression was correlated with lymph node metastasis, pathological staging, recurrence and metastasis, and the expression of Ki-67 protein (P<0.05 for all). The patients with high expression of MTDH and VEGF showed a lower DFS and OS (P<0.05 for both).

CONCLUSIONS

MTDH and VEGF expression may be correlated with tumor angiogenesis and progression and has the potential to be valuable prognostic factors in patients with TNBC.

BACKGROUND

Metadherin (MTDH) protein, also called astrocyte elevated gene-1 (AEG-1) is over expressed in a variety of malignant tumours, and is closely related to tumour invasion and the poor prognosis.

OBJECTIVE

This study tries to explore the clinical pathological significance of MTDH expression in a large cohort of patients with PTC.

METHODS

Immunohistochemistry was used to detect MTDH expression in 156 cases of PTC, 6 cases of anaplastic thyroid carcinoma (ATC), 10 cases of multinodular goitre (MNG) and 10 cases of thyroid adenoma tissues who received a thyroid operation between June 2003 and July 2008.

METHODS

Clinical pathological data of 156 cases of PTC were analysed according to MTDH expression. The Kaplan-Meier method was used to plot survival curves and log-rank test to compare the postoperative survival results. The prognostic meaning of MTDH expression in PTC was evaluated by Cox regression analysis.

RESULTS

The positive expression rates of MTDH in PTC and ATC tissues were 37·2% (58/156) and 50% (3/6), respectively, and MTDH positive expression rates were both 10% (1/10) in MNG and thyroid adenoma tissues. High MTDH expression in PTC was associated with larger tumour size (P = 0·030), high rates of lymph node (P = 0·041) and distant metastasis (P = 0·028), but no relation with the patient age, gender, tumour multicenter, extrathyroid invasion and tumour grade. High MTDH expression was associated with recurrence-free survival (RFS) and disease-specific survival rate (DSS) (P = 0·014, P = 0·001, respectively). Cox regression analysis showed that high MTDH expression was independent prognostic indicators for RFS and DSS in patients with PTC (P = 0·023 and P = 0·035, respectively).

CONCLUSIONS

High MTDH expression in PTC might play an important role in tumour growth and metastasis, and targeting MTDH treatment might have potential therapeutic value for patients with PTC.

Medulloblastoma (MB) is the most prevalent brain tumor that occurs during childhood and originates from cerebellar granule cell precursors. Based on recent studies, the differential expression of several microRNAs is involved in MB, while the role of microRNA-494 (miR-494) in MB remains unclear. Therefore, we conducted this study to investigate the regulative role of miR-494 in MB cells via the p38 mitogen-activated protein kinase (MAPK) signaling pathway by mediating c-myc. In the current study, MB cells were collected and transfected with miR-494 mimic, miR-494 inhibitor, siRNA- c-myc, and miR-494 inhibitor + siRNA-c-myc. The expressions of miR-494, c-myc, p38 MAPK, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), interleukin-6 (IL-6), metadherin (MTDH), phosphatase and tensin homolog (PTEN) and survivin were determined. Cell proliferation, cell-cycle distribution, apoptosis, migration, and invasion were evaluated. The results revealed that there was a poor expression of miR-494 and high expression of c-myc in MB tissues. C-myc was determined as the target gene of miR-494. In response to miR-494 mimic, MB cells were found to have increased Bax and PTEN expressions, as well as cell number in G1 phase and cell apoptosis and decreased c-myc, p38 MAPK, Bcl-2, MTDH, IL-6, and survivin expression and cell number count in the S phase, cell proliferation, migration, and invasion. In conclusion, the results demonstrated that the upregulation of miR-494 results in the suppression of cell proliferation, migration, and invasion, while it promotes apoptosis of MB cells through the negative mediation of c-myc, which in turn inactivates the p38 MAPK pathway.

Laryngeal carcinoma is one of the most common tumors concerning otorhinolaryngology head and neck surgery, however, the pathogenesis of laryngeal carcinoma remains unclear. MicroRNAs (miRNAs) have been reported to play vital roles in the pathogenesis of laryngeal carcinoma Herein, the present study was designed to explore the function and mechanism of miRNA‑98 in hypopharyngeal carcinoma. In brief, qRT‑PCR, MTT assay, western blot analysis, Transwell assay and luciferase reporter assay were performed. Based on the results, miRNA‑98 expression was downregulated in patients with hypopharyngeal carcinoma. Downregulation of miRNA‑98 promoted cell growth and migration, and decreased the apoptotic rate of hypopharyngeal carcinoma cells. Overexpression of miRNA‑98 increased the apoptotic rate, and inhibited cell growth and migration of hypopharyngeal carcinoma cells. Moreover, luciferase reporter assays revealed that MTDH is a direct target of miRNA‑98 and overexpression of miRNA‑98 induced the protein expression of PTEN and suppressed that of PI3K and p‑Akt. si‑MTDH attenuated the anticancer effects of miRNA‑98 on hypopharyngeal carcinoma via the PTEN/AKT pathway. To the best of our knowledge, the present study confirmed for the first time that miRNA‑98 inhibits hypopharyngeal carcinoma cell proliferation and induces apoptosis via the PTEN/AKT pathway by MTDH.

OBJECTIVE

Chromosomal alterations and copy number changes are frequent events in tumors, leading to amplification of focal regions containing several oncogenes. Gains and losses of several regions have been reported in head and neck cancer (HNC) but the copy number changes of the individual genes located in these regions have not been analyzed so far. In this study we aimed to analyze the copy number variations in patients with HNC.

METHODS

Prospective study SETTING: University hospital PARTICIPANTS: 50 patients with squamous cell carcinoma of the head and neck METHODS: Copy number changes and amplifications of 22 genes in tumors and matched tissue were analyzed by MLPA which allows simultaneous analysis of gene copy numbers in multiple genetic regions.

RESULTS

Amplifications were observed in 52% and losses were detected in 20% of the samples. Chromosome 8 was found to harbor the most frequent copy number alterations. The most frequently amplified genes were CCND1 and the MED1 genes followed by the MTDH and MYC genes on the long arm and ZNF703 on the short arm of chromosome 8. Amplification of the ZNF703, PRDM14 and MYC genes were highly correlated suggesting that the genes displaying high copy number changes on chromosome 8 collaborate during carcinogenesis.

CONCLUSIONS

The alterations found in our study supports the contribution of gene amplifications and indicate cooperation between certain oncogenes in the pathogenesis of HNSCC. Correlations between amplification of less familiar genes and known oncogenes warrant further investigation. This article is protected by copyright. All rights reserved.

Metadherin (MTDH) is a multifunctional oncogene involved in tumor cell migration and metastasis through regulating a number of oncogenic signaling pathways in various human malignancies. Previous studies have demonstrated that MTDH is overexpressed in human colorectal cancer (CRC) and associated with cancer progression and a poor prognosis. However, the underlying mechanisms remain largely unknown. The present study investigated the expression and role of MTDH in CRC cells as well as the underlying mechanism of this. Western blot analysis and quantitative polymerase chain reaction were conducted to determine protein and mRNA expression of MTDH in three human CRC cell lines. A short hairpin RNA (shRNA) targeting MTDH was introduced into CRC HCT116 cells to stably inhibit MTDH expression. A Cell Counting Kit‑8 assay, colony formation assay, Transwell assay and flow cytometry were used to investigate the effect of MTDH‑knockdown on cell proliferation, migration, apoptosis and cell cycle arrest. Western blotting was performed to examine the protein expression levels of cell growth‑ and apoptosis‑associated genes. The results demonstrated that MTDH was commonly expressed in CRC cell lines. MTDH silencing significantly suppressed cell growth, colony forming ability and migration while inducing the apoptosis of HCT116 cells. In addition, MTDH depletion induced S phase cell cycle arrest in HCT116 cells. Mechanistically, knockdown of MTDH markedly downregulated the expression of phosphorylated protein kinase B, c‑Myc, proliferating cell nuclear antigen and B‑cell lymphoma 2 (Bcl‑2) protein in HCT116 cells, and the expression of p53 and Bcl‑2‑associated X protein was significantly increased compared with the negative control shRNA group (P<0.05), suggesting that MTDH may function through the expression of numerous types of apoptosis‑associated and signaling channel proteins in CRC cells. Taken together, these data indicated that MTDH may serve as a biomarker and candidate therapeutic target for CRC.