Glioma is the most common primary brain tumor with poor prognosis. Effective treatment of glioma remains a big challenge due to complex pathogenic mechanisms. Previous studies have shown that metadherin (MTDH) and its interacting protein staphylococcal nuclease domain containing 1 (SND1) are overexpressed in many solid tumors. To elucidate the role of MDTH and SND1 in the pathogenesis of glioma, we examined the expression of MTDH and SND1 in primary glioma tissues and found that both MTDH and SND1 were highly expressed, with similar expression patterns. Co-expression of MTDH and SND1 was associated with advanced glioma grades. In addition, we detected the interaction between MTDH and SND1 in cultured glioma cell lines. MTDH could promote the expression of p65 and SND1 in glioma cells. However, enhanced SND1 expression by MTDH was abolished by the inhibition of p65. In conclusion, we demonstrated high expression levels MTDH and SND1 in primary glioma tissues. MTDH might promote glioma by inducing SND1 expression through the activation of NF-κB pathway. MTDH and SND1 may serve as the indicator of malignancy and prognosis as well as therapeutic targets for patients with glioma.

Metadherin (MTDH) can be recruited to mature tight junction complexes, and it regulates mesenchymal marker protein expression in many tumors and promote cancer metastasis. This study investigated the influence of MTDH expression on gastric cancer and to elucidate the potential mechanisms by which MTDH regulates actin cytoskeletal remodeling and enhances human gastric cancer metastasis via epithelial-mesenchymal transition (EMT). Relative MTDH mRNA expression levels were assessed by quantitative real-time PCR (Q-PCR), and MTDH protein expression levels and localization were evaluated via immunohistochemical (ICH) staining. We studied the role of MTDH in cancer cell migration and invasion by modulating MTDH expression in the gastric cancer cell lines MKN45 and AGS. We also confirmed the functions of MTDH through in vivo experiments. We found that MTDH expression levels were correlated with lymph node metastasis, TNM stages and decreased OS (P=0.002, <0.001 and 0.010, respectively) in human gastric cancer and that MTDH upregulation promoted EMT in vitro. Consistent with this finding, MTDH downregulation inhibited cell migration and invasion in vitro and suppressed tumor growth and metastasis in vivo. Furthermore, MTDH knockdown regulated actin cytoskeletal remodeling and inhibited EMT. Overall, our results provide a novel role for MTDH in regulating gastric cancer metastasis.

Micheliolide (MCL), derived from parthenolide (PTL), is known for its antioxidant and anti-inflammatory effects and has multiple roles in inflammatory diseases and tumours. To investigate its effect on renal disease, we intragastrically administrated DMAMCL, a dimethylamino Michael adduct of MCL for in vivo use, in two renal fibrosis models-the unilateral ureteral occlusion (UUO) model and an ischaemia-reperfusion injury (IRI) model and used MCL in combination with transforming growth factor beta 1 (TGF-β1) on mouse tubular epithelial cells (mTEC) in vitro. The expression of fibrotic markers (fibronectin and α-SMA) was remarkably reduced, while the expression of the epithelial marker E-cadherin was restored after DMAMCL treatment both in the UUO and IRI mice. MCL function in TGF-β1-induced epithelial-mesenchymal transition (EMT) in mTEC was consistent with the in vivo results. Metadherin (Mtdh) was activated in the fibrotic condition, suggesting that it might be involved in fibrogenesis. Interestingly, we found that while Mtdh was upregulated in the fibrotic condition, DMAMCL/MCL could suppress its expression. The overexpression of Mtdh exerted a pro-fibrotic effect by modulating the BMP/MAPK pathway in mTECs, and MCL could specifically reverse this effect. In conclusion, DMAMCL/MCL treatment represents a novel and effective therapy for renal fibrosis by suppressing the Mtdh/BMP/MAPK pathway.

Cholamine surface-modified gelatin nanoparticles prepared by the double desolvation method using acetone as a dehydrating agent were selected and potentially evaluated as non viral vectors of siRNA targeting a metastatic gene AEG-1 in MCF-7 breast carcinoma cells. The ability of modified gelatin nanoparticle to complex and deliver siRNA for gene silencing was investigated. Hence, Particle size, surface charge (zeta potential) and morphology of siRNA/Gelatin nanoparticles (siGNPs) were characterized via dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscope (TEM). Moreover, the nanoparticles cytotoxicity, loading efficiency and interaction with MCF-7 human breast carcinoma cells were evaluated. Cationized GNPs of mean size range of 174nm and PDI of 0.101 were produced. The loading efficiency of siGNPs at a Nitrogen/Phosphate (N/P) ratio (w/w) of 200:1 was approximately 96%. Cellular uptake was evaluated after FITC conjugation where the particles produced high transfection efficiency. Finally, ELISA analysis of AEG-1/MTDH expression demonstrated the gene silencing effect of siGNPs, as more than 75% MTDH protein were inhibited. Our data indicate that cholamine modified GNPs pose a promising non-viral siRNA carrier for altering gene expression in MCF-7 breast cancer cells with many advantages such as relatively high gene transfection efficiency and efficient silencing ability.

Metadherin (MTDH) was found to be highly expressed in various squamous cell carcinomas (SCCs); however, meta-analysis evaluating the association of MTDH in SCC has not been performed. The purpose of this study was to explore the biological functions of MTDH in esophageal squamous cell carcinoma (ESCC) and to meta-analyze the association between MTDH and SCC. Immunohistochemistry was performed to examine MTDH expression using an ESCC tissue array consisting of 86 ESCC and 78 paired normal adjacent tissues (NATs). MTDH was significantly overexpressed in ESCC tissues compared with NATs and was significantly associated with lymph node metastasis, differentiation, and prognosis. Knockdown of MTDH using an MTDH-short hairpin RNA plasmid caused cell cycle arrest at the G0/G1 phase and induced apoptosis of EC9706 cells. Knockdown of MTDH suppressed the proliferation, invasion, and migration of ESCC cells. Furthermore, meta-analysis revealed that overexpression of MTDH was significantly associated with the lymph node metastasis, advanced clinical stage, and T classification of tissues in SCC, suggesting that MTDH might be used as a potential therapeutic target in the lymph node metastasis of ESCC.

It has been reported that Retinoic acid receptor responder 3 (RARRES3) could suppress the metastasis of colorectal cancer (CRC). However, the underlying mechanism by which RARRES3 suppresses metastasis remains unknown. To investigate the functional involvement of RARRES3 in CRC, we first analyzed the expression of this protein between human CRC clinical samples and their corresponding normal controls and tested its correlation with clinicopathology as well as prognosis of CRC. We also examined the endogenous expression of RARRES3 by western-blot in a panel of CRC cell lines with different metastatic capacity. Cell proliferation, migration and invation of the CRC cell lines with either knockdown or reexpression of RARRES3 were examined by MTT, transwell and wound healing assays, respectively. The intrecellular signaling pathways affected by manipulations of RARRES3 in CRC cells were determined by western blot. Immunoprecipitation (IP) was employed to assess the interactionbetween proteins. To investigate the metastatic ability in vivo, CRC cell lines with manipulations of RARRES3 expression were inoculated in nude mice through tail vein injection. We confirmed that RARRES3 was significantly down-regulated in CRC tissues compared with normal controls. RARRES3 expression was not correlated with prognosis but significantly associated with CRC differentiation and lymphnodes metastases. We also found that RARRES3 was able to significantly suppress the metastasis of CRC cells both in vitro and in vivo through the regulation of epithelial-mesenchymal transition (EMT) process during which RARRES3 interactedwith MTDH in an opposite way. Taken together, we for the first time found that RARRES3 was able to suppress the metastasis of CRC both in vitro and in vivo via suppression of MTDH so as to regulate EMT.

Dysregulation of miR-1297 has been detected in various human cancers, and miR-1297 can function as either an oncogene or tumor suppressor. However, the role of miR-1297 in pancreatic adenocarcinoma has not been previously reported. Here, we investigated miR-1297 expression in pancreatic cancer and the role it plays in the development and metastasis of pancreatic adenocarcinoma. In the present study, MiR-1297 and metadherin (MTDH) expression in pancreatic cancer tissue was detected using quantitative real-time PCR (qRT-PCR) and western blot methods. The CCK-8 assay and EdU incorporation assay were used to analyze the impact of miR-1297 and MTDH on cell proliferation. Flow cytometric and Hoechst 33342 staining methods were used to explore how miR-1297 and MTDH affect cell apoptosis. The Transwell assay and scratch wound healing assay were used to analyze cell migration and invasion capabilities. The dual-luciferase assay was used to confirm that miR-1297 targets MTDH. Here, we found that miR-1297 expression was decreased in pancreatic adenocarcinoma tissues, while MTDH expression was increased in those tissues. Furthermore, western blot and dual-luciferase assay results confirmed that MTDH was a direct target of miR-1297. Additionally, overexpression of miR-1297 or knockdown of MTDH suppressed BxPC-3 and PANC-1 cell proliferation, and upregulation of miR-1297 or suppression of MTDH promoted BxPC-3 and PANC-1 cell apoptosis. Finally, BxPC-3 and PANC-1 cell migration and invasion abilities were suppressed by either overexpression of miR-1297 or downregulation of MTHD. In conclusion, our results suggest that miR-1297 inhibits the growth and metastasis of pancreatic adenocarcinoma by downregulating MTDH expression, and the miR-1297/MTDH pathway is a potential target for treating pancreatic adenocarcinoma.

Recent molecular advances have identified a novel, clinically aggressive subgroup of undifferentiated round cell sarcomas defined molecularly by oncogenic fusion of the gene, CIC, and either DUX4 or its paralog, DUX4L, herein termed CIC-DUX sarcomas. Morphologically, CIC-DUX sarcomas are round cell sarcomas with high-grade nuclear features, including vesicular chromatin and nucleoli, patchy clear cell foci, myxoid change, and necrosis. Here, we studied a cohort of 10 cases, including 6 newly identified cases, 2 with paired metastases. Given our prior observation of trisomy 8 in these tumors, we assayed for amplification and expression of MYC (c-Myc) and representative downstream targets. Trisomy 8 was detected in 5/7 testable cases, with further amplification of MYC locus in 6/7 testable cases and immunohistochemical expression of MYC in 10/10. The canonical MYC transcriptional target, p21, but not MTDH, was differentially expressed compared with Ewing sarcomas. Given prior observation of induction of ETS-family transcription factors by the fusion oncoprotein, we assayed and identified highly prevalent positivity for ERG (9/10) and FLI1 (8/8). These findings are cautionary regarding use of these immunostains in prospective case workup, whereas the prevalent MYC amplification may represent a therapeutically targetable oncogenic pathway in CIC-DUX sarcomas.

Accumulating data suggest that metadherin (MTDH) may function as an oncogene. Our previous study showed that MTDH promotes hepatocellular carcinoma (HCC) metastasis via the epithelial-mesenchymal transition. In this study, we aim to further elucidate how MTDH promotes HCC metastasis. Using Co-immunoprecipitation (co-IP) and mass spectrometry, we found that MTDH can specifically bind to protein arginine methyltransferase 5 (PRMT5). Further functional assays revealed that PRMT5 overexpression promoted the proliferation and motility of HCC cells and that knockout of PRMT5 impeded the effect of MTDH. The immunohistochemistry assay/tissue microarray results showed that when MTDH was overexpressed in HCC cells, PRMT5 translocated from the nucleus to the cytoplasm, with the subsequent translocation of β-catenin from the cytoplasm to the nucleus and upregulation of the WNT-β-catenin signaling pathway. Further in vivo experiments suggested that PRMT5 and β-catenin played a pivotal role in MTDH-mediated HCC metastasis. We therefore concluded that the MTDH-PRMT5 complex promotes HCC metastasis by regulating the WNT-β-catenin signaling pathway.

BACKGROUND

Breast cancer is a leading cause of death in women and with an increasing worldwide incidence. Doxorubicin, as a first-line anthracycline-based drug is conventional used on breast cancer clinical chemotherapy. However, the drug resistances limited the curative effect of the doxorubicin therapy in breast cancer patients, but the molecular mechanism determinants of breast cancer resistance to doxorubicin chemotherapy are not fully understood. In order to explore the association between metadherin (MTDH) and doxorubicin sensitivity, the differential expressions of MTDH in breast cancer cell lines and the sensitivity to doxorubicin of breast cancer cell lines were investigated.

METHODS

The mRNA and protein expression of MTDH were determined by real-time PCR and Western blot in breast cancer cells such as MDA-MB-231, MCF-7, MDA-MB-435S, MCF-7/ADR cells. Once MTDH gene was knocked down by siRNA in MCF-7/ADR cells and overexpressed by MTDH plasmid transfection in MDA-MB-231 cells, the cell growth and therapeutic sensitivity of doxorubicin were evaluated using MTT and the Cell cycle assay and apoptosis rate was determined by flow cytometry.

RESULTS

MCF-7/ADR cells revealed highly expressed MTDH and MDA-MB-231 cells had the lowest expression of MTDH. After MTDH gene was knocked down, the cell proliferation was inhibited, and the inhibitory rate of cell growth and apoptosis rate were enhanced, and the cell cycle arrest during the G0/G1 phase in the presence of doxorubicin treatment. On the other hand, the opposite results were observed in MDA-MB-231 cells with overexpressed MTDH gene.

CONCLUSIONS

MTDH gene plays a promoting role in the proliferation of breast cancer cells and its high expression may be associated with doxorubicin sensitivity of breast cancer.

Increased expression of metadherin (MTDH, also known as AEG-1 and 3D3/LYRIC) has been associated with drug resistance, metastasis, and angiogenesis in a variety of cancers. However, the specific mechanisms through which MTDH is involved in these processes remain unclear. To uncover these mechanisms, we generated Mtdh knock-out mice via a targeted disruption of exon 3. Homozygous Mtdh knock-out mice are viable, but males are infertile. The homozygous male mice present with massive loss of spermatozoa as a consequence of meiotic failure. Accumulation of γ-H2AX in spermatocytes of homozygous Mtdh knock-out mice confirms an increase in unrepaired DNA breaks. We also examined expression of the DNA repair protein Rad18, which is regulated by MTDH at the post-transcriptional level. In testes from Mtdh exon 3-deficient mice, Rad18 foci were increased in the lumina of the seminiferous tubules. The Piwi-interacting RNA (piRNA)-interacting protein Mili was expressed at high levels in testes from Mtdh knock-out mice. Accordingly, genome-wide small RNA deep sequencing demonstrated altered expression of piRNAs in the testes of Mtdh knock-out mice as compared with wild type mice. In addition, we observed significantly reduced expression of microRNAs (miRNAs) including miR-16 and miR-19b, which are known to be significantly reduced in the semen of infertile men. In sum, our observations indicate a crucial role for MTDH in male fertility and the DNA repair mechanisms required for normal spermatogenesis.

Background: Recently, microRNA-877-5p (miR-877) was recognized as a cancer-associated miRNA in hepatocellular and renal cell carcinomas. However, little is known regarding its expression pattern and role in colorectal cancer (CRC) tumorigenesis. Material and methods: In the present study, reverse-transcription quantitative polymerase chain reaction was performed to detect miR-877 expression in CRC tissues and cell lines. A series of functional experiments were used to determine the effects of miR-877 upregulation on CRC cell proliferation, colony formation, apoptosis, migration, and invasion. In addition, the regulatory role of miR-877 in tumor growth was examined in vivo using a xenograft experiment. More importantly, the mechanisms underlying the action of miR-877 in CRC were explored. Results: A significant decrease in the expression of miR-877 was observed in CRC tissues and cell lines. Low miR-877 expression correlated with lymph node metastasis and TNM stage of CRC patients. Functional experiments revealed that ectopic expression of miR-877 suppressed CRC cell proliferation and colony formation ability, induced cell apoptosis, inhibited cell migration and invasion in vitro, and reduced tumor growth in vivo. Metadherin (MTDH) was recognized as a direct target of miR-877 in CRC cells. It was notably overexpressed in CRC tissues, and its expression was inversely correlated with that of miR-877 expression. Furthermore, MTDH knockdown simulated the tumor suppressor activity of miR-877 in CRC cells. MTDH restoration impaired the suppressive effects of miR-877 on malignant phenotypes of CRC cells. In addition, miR-877 inhibited the activation of the PTEN/Akt signaling pathway by regulating MTDH expression both in vitro and in vivo. Conclusion: Collectively, these results demonstrate that miR-877 inhibits the progression of CRC, at least partly by the direct targeting of MTDH and regulation of the PTEN/Akt pathway. Thus, miR-877 may serve as a potential therapeutic target for the treatment of patients with CRC.

It has been reported that IL-8 was involved in the promotion of invasion of Gastric Cancer (GC), however the underlying mechanism by which IL-8 was observed to be able to promote invasion remains unknown. Here, in our study, IL-8 was shown to be significantly up-regulated in GC compared with paired normal control tissues whose expression was markedly associated with inferior overall prognosis; and IL-8 was displayed to be capable of directly interacting with metadherin (MTDH), which in turn can up-regulate IL-8 expression. Blockage of IL-8/MTDH using specific mono-antibody can abolish the invasion IL-8 mediated. Taken together, our results may provide a novel explanation of working mechanism of IL-8 in the invasion of GC.

Numerous studies have reported that the role played by miR-26a in cancer is controversial, but whether miR-26a regulates metadherin (MTDH) expression in esophageal squamous cell carcinoma (ESCC) is unclear. We performed this study to investigate the clinical relevance of miR-26a expression in ESCC. miR-26a was detected by using the in situ hybridization method. To functionally analyze the role of miR-26a in ESCC cell lines in vitro, KYSE-450 and Eca109 cells were employed, whose endogenous miR-26a was artificially down- or up-regulated, respectively, by using lentiviral-based transfection. There was significant association between miR-26a expression and clinical stage (P = 0.049), lymph node metastasis (P = 0.023), tumor volume (P = 0.003), and poor overall prognosis (P = 0.026). miR-26a was able to suppress proliferation and migration of ESCC cells in vitro Moreover, we have confirmed that miR-26a can negatively regulate MTDH in ESCC cells by using luciferase reporter assay. In addition, to investigate the role miR-26a plays in cell proliferation, we nude mice were xenografted with ESCC cells whose miR-26a was stably down- and up-regulated. Together, our results show that miR-26a is capable of suppressing the proliferation and migration of ESCC cells via negative regulation of MTDH. Moreover, miR-26a expression was clinically relevant in cancer progression and poor prognosis, which supports the idea that miR-26a acts as a tumor suppressor in ESCC.-Yang, C., Zheng, S., Liu, T., Liu, Q., Dai, F., Zhou, J., Chen, Y., Sheyhidin, I., Lu, X. Down-regulated miR-26a promotes proliferation, migration, and invasion via negative regulation of MTDH in esophageal squamous cell carcinoma.

As an AEG-1/MTDH/LYRIC-binding protein, Staphylococcal nuclease domain-containing 1 (SND1) is upregulated in numerous human cancers where it has been assigned multiple functional roles. In this study, we discovered that SND1 was upregulated in breast cancer tissues, particularly the tissues from patients with distant metastases. The underlying molecular mechanisms demonstrated a novel role of SND1 in regulating the activity of transforming growth factor β1 (TGFβ1) signaling pathway, which promotes metastasis in breast cancer. We illustrated that SND1 physically associated with and recruited the histone acetylase GCN5 to the promoter regions of Smad2/3/4, and consequently enhanced the gene transcriptional activation of Smad2/3/4, which are essential downstream regulators in the TGFβ1 pathway. An electrophoretic mobility shift assay experiment further verified that SND1 could recognize the conserved domains (motifs 1 and 2) in the promoter regions of the Smad genes. Glutathione S-transferase (GST) pulldown assays indicated that the tudor domain of SND1 was responsible for the recruitment of GCN5, which increased histone H3K9 acetylation. Consistent with these results, a loss-of-function of SND1 reduced the protein level of Smads and the phosphorylation of R-Smads, thereby attenuating the R-Smad/Co-Smad depended transcription and, as a result, inhibited TGFβ signaling activation.

BACKGROUND

Accumulating studies have reported the abnormal expression of microRNA-136 (miR-136) in numerous types of human cancer, and its involvement in cancer initiation and progression. However, there are no investigations of miR-136 in osteosarcoma (OS).

OBJECTIVE

To explore the expression pattern, clinical significance and potential roles of miR-136 in OS.

METHODS

miR-136 expression in clinical OS tissues and human OS cell lines were detected by qPCR, and its associations with clinicopathological characteristics of OS patients were statistically analyzed. Then, the effects of miR-136 on OS cell proliferation, migration and invasion were assessed in vitro. Its underling mechanisms were also investigated.

RESULTS

miR-136 expression in OS tissues and cells were dramatically decreased compared with corresponding non-cancerous tissues and cells, respectively. Low miR-136 expression was significantly associated with aggressive clinical features, including the advanced clinical stage, the presence of lung and distant metastasis (all P< 0.05). Additionally, enforced expression of miR-136 obviously inhibited the proliferation, migration and invasion of OS cells in vitro. Mechanistically, metadherin (MTDH) was predicted and verified as a target gene of miR-136. Further functional experiments indicated that the loss of MTDH abrogated the tumor suppressive roles of miR-136 in OS cells.

CONCLUSIONS

Our findings provide the first evidence that the aberrant expression of miR-136 may be implicated into carcinogenesis and cancer progression of OS. Functionally, miR-136 may inhibit the proliferation, migration and invasion of OS cells via negatively regulating its target gene MTDH. Thus, miR-136-MTDH axis may be a potential therapeutic targets for the treatment of OS.

Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death driven by lipid hydroperoxides within biological membranes. Although therapy-resistant mesenchymal-high cancers are particularly vulnerable to ferroptosis inducers, especially phospholipid glutathione peroxidase 4 (GPx4) inhibitors, the underlying mechanism is yet to be deciphered. As such, the full application of GPx4 inhibitors in cancer therapy remains challenging. Here we demonstrate that metadherin (MTDH) confers a therapy-resistant mesenchymal-high cell state and enhanced sensitivity to inducers of ferroptosis. Mechanistically, MTDH inhibited GPx4, as well as the solute carrier family 3 member 2 (SLC3A2, a system X_c^- heterodimerization partner), at both the messenger RNA and protein levels. Our metabolomic studies demonstrated that MTDH reduced intracellular cysteine, but increased glutamate levels, ultimately decreasing levels of glutathione and setting the stage for increased vulnerability to ferroptosis. Finally, we observed an enhanced antitumor effect when we combined various ferroptosis inducers both in vitro and in vivo; the level of MTDH correlated with the ferroptotic effect. We have demonstrated for the first time that MTDH enhances the vulnerability of cancer cells to ferroptosis and may serve as a therapeutic biomarker for future ferroptosis-centered cancer therapy.

The enormity and complexity of cancer genome data present significant challenges in downstream validation of novel oncogenes and tumor suppressors. In this issue of Cancer Cell, Hu et al. evaluate candidate oncogenes in a recurrent amplification in poor-prognosis breast cancers. They identify and validate the prometastatic gene metadherin (MTDH) as a key modulator of endothelial adhesion and chemoresistance.

MicroRNAs (miRNAs) are a group of non-protein-coding, highly conserved single-stranded RNA molecules. The abnormal expression of miRNAs has been demonstrated to have an important function in the carcinogenesis and progression of gastric cancer. microRNA-154 (miR-154) has been reported to be downregulated in non-small cell lung, colorectal and prostate cancer. However, the expression and roles of miR-154 in gastric cancer remain to be established. The present study measured the expression levels of miR-154 in gastric cancer tissues and cell lines. miR-154 was found to be significantly downregulated in gastric cancer tissues and cell lines. In addition, functional studies indicated that the overexpression of miR-154 inhibited the proliferation, migration and invasion of gastric cancer cells. Using TargetScan, a dual luciferase reporter assay, reverse transcription-quantitative polymerase chain reaction and western blot analysis, metadherin (MTDH) was revealed as a novel miR-154 target. In addition, knocking down MTDH lead to a similar effect as overexpressing-154 in gastric cells. The present findings indicate that miR-154 was downregulated in gastric cancer, and inhibited tumor behaviors of gastric cancer cells partially through the downregulation of MTDH. Therefore, the miR-154/MTDH axis may be a novel therapeutic to treat patients with gastric cancer.

Metastatic ovarian cancer has a dismal prognosis and current chemotherapeutic approaches have very limited success. Metadherin (MTDH) is expressed in human ovarian cancer tissue and its expression inversely correlates with patients overall survival. Consistent with these studies, we observed MTDH expression in tissue specimens of FIGO Stage III ovarian carcinomas (72/83 cases). However, we also observed this in normal human ovarian epithelial (OE) cells, which raised the question of whether MTDH-variants with functional differences exist. We identified a novel MTDH exon 11 skipping variant (MTDHdel) which was seen at higher levels in ovarian cancer compared to benign OE cells. We analyzed MTDH-binding partner interactions and found that 12 members of the small ribosomal subunit and several mRNA binding proteins bound stronger to MTDHdel than to wildtype MTDH which indicates differential effects on gene translation. Knockdown of MTDH in ovarian cancer cells reduced the amount of distant metastases and improved the survival of ovarian cancer-bearing mice. Selective overexpression of the MTDHdel enhanced murine and human ovarian cancer progression and caused a malignant phenotype in originally benign human OE cells. MTDHdel was detectable in microdissected ovarian cancer cells of some human tissue specimens of ovarian carcinomas. In summary, we have identified a novel MTDH exon 11 skipping variant that shows enhanced binding to small ribosomal subunit members and that caused reduced overall survival of ovarian cancer bearing mice. Based on the findings in the murine system and in human tissues, MTDHdel must be considered a major promalignant factor for ovarian cancer.

Expression of AEG-1 (also known as MTDH or LYRIC) is elevated in many cancers including glioblastoma multiforme (GBM), in which it functions as an oncogene. AEG-1 activates AKT signaling and physically interacts with AKT2 in GBM. Disruption of this interaction reduces glioma cell survival and invasion, uncovering a novel potential target for development of an effective therapy against GBM.

BACKGROUND

The multiple tyrosine kinase inhibitors SU6668 have a promising therapeutic effect on the progression of hematological malignancies and some solid tumors. Here, we determined its effect on triple negative breast cancer (TNBC) cells and explored the potential molecular mechanism.

METHODS

In this study, MDA-MB-231 cells were treated with SU6668 (15 μM, 30 μM) for 72 h and the change of proliferation was examined by MTT and tablet cloning. DNA ploidy was detected by flow cytometric analysis with PI staining. Double-label immunofluorescence method was used to detect the expression and distribution of MTDH proteins. VEGFR2, HIF-1α, MTDH, E-cadhrein, and SMA expressions were detected by Western bolt assay.

RESULTS

This study showed that SU6668 inhibited the proliferation and induced polyploidization of MDA-MB-231 cells in a dose dependent form. SU6668 exposure increased the distribution of MTDH in cytoplasm and decreased its distribution in nuclei. After the treatment of SU6668, VEGFR2, HIF-1α, MTDH and SMA proteins were down-regulated, while E-cadhrein was up-regulated in MDA-MB-231 cells.

CONCLUSIONS

In conclusion, SU6668 exposure maybe induces polyploidization, inhibit EMT and influence the expression of MTDH, which suppresses the proliferation in TNBC cells. MTDH is a key signal protein in downstream of VEGF/HIF-1αpathway in MDA-MB-231 cells, which may be used as the potential target in the treatment of TNBC.

Gastric cancer is the fifth most frequent malignancy and the fourth most common cause of cancer‑associated mortality worldwide. MicroRNAs (miRNAs) are a group of small RNAs that regulate several cellular processes. In particular, a large number of miRNAs are involved in gastric cancer formation and progression. Thus, miRNAs may be considered as effective diagnostic biomarkers and therapeutic methods for gastric cancer. The aim of the current study was to detect miRNA (miR)‑197 expression in gastric cancer and to investigate its biological role and associated mechanism in gastric cancer. In the present study, miR‑197 expression was demonstrated to be considerably downregulated in gastric cancer tissues and cell lines. Its low expression level was associated with tumour size, invasive depth, tumour‑node‑metastasis staging and lymph node metastasis. High expression of miR‑197 inhibited tumour cell proliferation and invasion in vitro. Subsequently, metadherin (MTDH) was identified as a direct target gene of miR‑197 in gastric cancer, and this was confirmed by bioinformatics analysis, Dual‑luciferase reporter assay, reverse transcription quantitative polymerase chain reaction and western blot analysis. MTDH expression was upregulated in gastric cancer and was inversely correlated with miR‑197 expression levels. In addition, MTDH overexpression prevented the proliferation and inhibited invasion induced by miR‑197 overexpression. In addition, miR‑197 was demonstrated to regulate the phosphatase and tensin homolog (PTEN)/AKT signalling pathway in gastric cancer. The results of the present study suggested that miR‑197 serves a tumour‑suppressing role in human gastric carcinogenesis and progression by regulating the MTDH/PTEN/AKT signalling pathway. The miR‑197/MTDH axis may provide a novel effective therapeutic target for patients with gastric cancer.

Background: MicroRNA-876-5p (miR-876) dysregulation contributes to the aggressiveness of various types of human cancer. This study was aimed at measuring miR-876 expression in breast cancer, determining the specific roles of miR-876 in the progression of breast cancer and understanding the corresponding molecular mechanisms. Materials and methods: miR-876 expression in breast cancer tissues and cell lines was quantified via RT-qPCR. The effect of miR-876 upregulation on the malignant phenotype of breast cancer cells was investigated using CCK-8 assays, flow cytometry, Transwell migration and invasion assays and tumor xenograft experiments. The mechanisms underlying the tumor-suppressive action of miR-876 in breast cancer cells were explored using bioinformatic analysis, luciferase reporter assays, RT-qPCR and Western blot analysis. Results: miR-876 was found to be underexpressed in breast cancer tissues and cell lines. Decreased miR-876 expression notably correlated with lymphatic invasion metastasis, TNM stage and differentiation grade. Overall survival was lower among patients with breast cancer and low miR-876 expression than in patients with high miR-876 expression. Restoration of miR-876 expression decreased breast cancer cell proliferation, migration and invasion in vitro and restricted tumor growth in vivo as well as increased cell apoptosis. Metadherin (MTDH) was identified as a novel target of miR-876 in breast cancer cells. Furthermore, long intergenic nonprotein-coding RNA 707 (LINC00707) acted as a molecular sponge for miR-876, thereby regulating MTDH expression in breast cancer. Finally, silencing miR-876 expression attenuated the influence of a LINC00707 knockdown on the malignancy of breast cancer cells. Conclusion: This study, thus, revealed the vital functions of the LINC00707-miR-876-MTDH pathway in breast cancer and provided attractive targets and markers for its treatment.