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Long noncoding RNAs (lncRNAs) play a significant role in the occurrence and development of malignant tumours. However, ceRNAs, which are significantly associated with the prognosis of breast cancer (BC), need to be further investigated. Therefore, the current study aimed to investigate the effect of the lncRNA DDX11-AS1 on BC progression. Bioinformatics analysis via a public microarray revealed that DDX11-AS1 was upregulated in BC. The above findings were verified via RT‒qPCR analysis of BC tissues. Additionally, our study revealed that the expression levels of DDX11-AS1 increased with increasing pathological grade and lymph node metastasis. Furthermore, DDX11-AS1 knockdown markedly inhibited the proliferation, migration and invasion abilities of BC cells. Mechanistically, DDX11-AS1 could prevent the degradation of MTDH in BC via competitively binding with miR-30c-5p, which could act as a tumour promoter factor. Additionally, miR-30c-5p was downregulated and MTDH was upregulated in BC cells and tissues. The promoting effect of DDX11-AS1 on BC cells was enhanced by miR-30c-5p silencing and reduced by treatment with MTDH inhibitors. Collectively, the above results suggest that the DDX11-AS1/miR-30c-5p/MTDH axis could be associated with the progression of BC and that DDX11-AS1 could be a potential biomarker and therapeutic target for BC. [ABSTRACT FROM AUTHOR]

Abstract Long noncoding RNAs (lncRNAs) play a significant role in the occurrence and development of malignant tumours. However, ceRNAs, which are significantly associated with the prognosis of breast cancer (BC), need to be further investigated. Therefore, the current study aimed to investigate the effect of the lncRNA DDX11-AS1 on BC progression. Bioinformatics analysis via a public microarray revealed that DDX11-AS1 was upregulated in BC. The above findings were verified via RT‒qPCR analysis of BC tissues. Additionally, our study revealed that the expression levels of DDX11-AS1 increased with increasing pathological grade and lymph node metastasis. Furthermore, DDX11-AS1 knockdown markedly inhibited the proliferation, migration and invasion abilities of BC cells. Mechanistically, DDX11-AS1 could prevent the degradation of MTDH in BC via competitively binding with miR-30c-5p, which could act as a tumour promoter factor. Additionally, miR-30c-5p was downregulated and MTDH was upregulated in BC cells and tissues. The promoting effect of DDX11-AS1 on BC cells was enhanced by miR-30c-5p silencing and reduced by treatment with MTDH inhibitors. Collectively, the above results suggest that the DDX11-AS1/miR-30c-5p/MTDH axis could be associated with the progression of BC and that DDX11-AS1 could be a potential biomarker and therapeutic target for BC.

The unfolded protein response is an intricate system of sensor proteins in the endoplasmic reticulum (ER) that recognizes misfolded proteins and transmits information via transcription factors to either regain proteostasis or, depending on the severity, to induce apoptosis. The main transmembrane sensor is IRE1α, which contains cytoplasmic kinase and RNase domains relevant for its activation and the mRNA splicing of the transcription factor XBP1. Mast cell leukemia (MCL) is a severe form of systemic mastocytosis. The inhibition of IRE1α in the MCL cell line HMC-1.2 has anti-proliferative and pro-apoptotic effects, motivating us to elucidate the IRE1α interactors/regulators in HMC-1.2 cells. Therefore, the TurboID proximity labeling technique combined with MS analysis was applied. Gene Ontology and pathway enrichment analyses revealed that the majority of the enriched proteins are involved in vesicle-mediated transport, protein stabilization, and ubiquitin-dependent ER-associated protein degradation pathways. In particular, the AAA ATPase VCP and the oncoprotein MTDH as IRE1α-interacting proteins caught our interest for further analyses. The pharmacological inhibition of VCP activity resulted in the increased stability of IRE1α and MTDH as well as the activation of IRE1α. The interaction of VCP with both IRE1α and MTDH was dependent on ubiquitination. Moreover, MTDH stability was reduced in IRE1α-knockout cells. Hence, pharmacological manipulation of IRE1α–MTDH–VCP complex(es) might enable the treatment of MCL. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) play essential roles in the development and progression of many cancers. However, the contributions of lncRNAs to medulloblastoma (MB) remain poorly understood. Here, we identify Miat as an lncRNA enriched in the sonic hedgehog group of MB that is required for maintenance of a treatment-resistant stem-like phenotype in the disease. Loss of Miat results in the differentiation of tumor-initiating, stem-like MB cells and enforces the differentiation of tumorigenic stem-like MB cells into a nontumorigenic state. Miat expression in stem-like MB cells also facilitates treatment resistance by down-regulating p53 signaling and impairing radiation-induced cell death, which can be reversed by therapeutic inhibition of Miat using antisense oligonucleotides. Mechanistically, the RNA binding protein Metadherin (Mtdh), previously linked to resistance to cytotoxic therapy in cancer, binds to Miat in stem-like MB cells. Like the loss of Miat, the loss of Mtdh reduces tumorigenicity and increases sensitivity to radiation-induced death in stem-like MB cells. Moreover, Miat and Mtdh function to regulate the biogenesis of several microRNAs and facilitate tumorigenesis and treatment resistance. Taken together, these data reveal an essential role for the lncRNA Miat in sustaining a treatment-resistant pool of tumorigenic stem-like MB cells.

In perinatal medicine, intrauterine growth restriction (IUGR) is one of the greatest challenges. The etiology of IUGR is multifactorial, but most cases are thought to arise from placental insufficiency. However, identifying the placental cause of IUGR can be difficult due to numerous confounding factors. Selective IUGR (sIUGR) would be a good model to investigate how impaired placentation affects fetal development, as the growth discordance between monochorionic twins cannot be explained by confounding genetic or maternal factors. Herein, we constructed and analyzed the placental proteomic profiles of IUGR twins and normal cotwins. Specifically, we identified a total of 5481 proteins, of which 233 were differentially expressed (57 up-regulated and 176 down-regulated) in IUGR twins. Bioinformatics analysis indicates that these differentially expressed proteins (DEPs) are mainly associated with cardiovascular system development and function, organismal survival, and organismal development. Notably, 34 DEPs are significantly enriched in angiogenesis, and diminished placental angiogenesis in IUGR twins has been further elaborately confirmed. Moreover, we found decreased expression of metadherin (MTDH) in the placentas of IUGR twins and demonstrated that MTDH contributes to placental angiogenesis and fetal growth in vitro. Collectively, our findings reveal the comprehensive proteomic signatures of placentas for sIUGR twins, and the DEPs identified may provide in-depth insights into the pathogenesis of placental dysfunction and subsequent impaired fetal growth.

Triple‐negative breast cancer (TNBC) has an aggressive clinical course, and paclitaxel (PTX)‐based chemotherapy remains the main therapeutic drug. Metadherin (MTDH) acts as an oncogene that regulates proliferation, invasion, metastasis, and chemoresistance. This study aimed to investigate whether TNBC chemosensitivity to PTX was related to the MTDH/AKT/glycogen synthase kinase‐3beta (GSK‐3β) pathway. Clinical baseline characteristics and immunohistochemistry (IHC) were used to evaluate the expression and prognosis of MTDH and AKT (protein kinase B, PKB) in TNBC patient samples. MTDH shRNA, MTDH overexpression vector, MK‐2206, and PTX intervention were used in cell models and mouse tumor‐bearing models. Afterwards, mRNA and protein levels were assessed using quantitative real‐time polymerase chain reaction and Western blot. Evaluate the level of tumor cell apoptosis and cell cycle using flow cytometry. Cell viability was detected using Cell Count Kit 8. The in vivo imaging system is used to analyze the growth of tumors. We found that higher expression of MTDH or AKT resulted in poorer disease‐free survival and a lower Miller–Payne grade. MTDH promotes cell proliferation and increases p‐AKT and p‐GSK‐3β expression in TNBC cells. Notably, suppression of AKT terminated MTDH overexpression‐induced cell proliferation and apoptosis. MTDH knockdown or the AKT inhibitor MK2206 reduced the p‐AKT and p‐GSK‐3β ratio, reduced cell viability and proliferation, increased cell apoptosis, and increased chemosensitivity to PTX. In vivo, xenograft tumors of an MTDH knockdown+MK2206 group treated with PTX were the smallest compared to other groups. In short, MTDH inhibits TNBC chemosensitivity to PTX by activating the AKT/GSK‐3β signaling pathway. [ABSTRACT FROM AUTHOR]

Background and purpose: Long non-coding RNA small nucleolar RNA host gene 5 (lncRNA SNHG5) plays a cancer-promoting role in many cancers, however its effect on colorectal cancer (CRC) and its regulatory mechanism are not clear. This study aimed to explore the mechanism of lncRNA SNHG5/miR-26a-5p/metadherin (MTDH) signal axis promoting metastasis of CRC. Methods: The data of The Cancer Genome Atlas (TCGA) database was analyzed, the abnormal expression of lncRNA in CRC was explored and analyzed the survival. Samples of CRC, paracancerous tissues and complete clinical data of patients who underwent surgical resection from October 2012 to October 2016 were collected. The expression levels of SNHG5 and miR-26a-5p in lncRNA were detected by real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR), and the expression level of MTDH was detected by immunohistochemistry. The relationship between the relative expression level of lncRNA SNHG5 in CRC and clinicopathological features and survival time was analyzed. The effects of lncRNA SNHG5 on the proliferation, migration and invasion of CRC cells were detected by cell counting kit-8 (CCK-8), clone formation, scratching assays, transwell test and in vivo xenotransplantation. The relationship between CRC cell metastasis, the expression level of epithelial-mesenchymal transition related molecules and lncRNA SNHG5 expression level by Western blot and immunohistochemical detection were explored. The physical interaction between SNHG5 and miR-26a-5p, MTDH and miR-26a-5p was studied by RNA pull-down test, double luciferase reporter gene detection and RNA co-immunoprecipitation. The functional relationship among the three was verified by CCK-8, EdU and transwell experiments. The effect of SNHG5, miR-26a-5p and MTDH expression on migration and invasion related molecules was analyzed by Western blot. Results: The results of TCGA database analysis showed that lncRNA SNHG5 was significantly upregulated in CRC. The results of RTFQ-PCR and immunohistochemistry showed that the levels of lncRNA SNHG5 and MTDH in CRC tissues were significantly upregulated (P

The unfolded protein response is an intricate system of sensor proteins in the endoplasmic reticulum (ER) that recognizes misfolded proteins and transmits information via transcription factors to either regain proteostasis or, depending on the severity, to induce apoptosis. The main transmembrane sensor is IRE1α, which contains cytoplasmic kinase and RNase domains relevant for its activation and the mRNA splicing of the transcription factor XBP1. Mast cell leukemia (MCL) is a severe form of systemic mastocytosis. The inhibition of IRE1α in the MCL cell line HMC-1.2 has anti-proliferative and pro-apoptotic effects, motivating us to elucidate the IRE1α interactors/regulators in HMC-1.2 cells. Therefore, the TurboID proximity labeling technique combined with MS analysis was applied. Gene Ontology and pathway enrichment analyses revealed that the majority of the enriched proteins are involved in vesicle-mediated transport, protein stabilization, and ubiquitin-dependent ER-associated protein degradation pathways. In particular, the AAA ATPase VCP and the oncoprotein MTDH as IRE1α-interacting proteins caught our interest for further analyses. The pharmacological inhibition of VCP activity resulted in the increased stability of IRE1α and MTDH as well as the activation of IRE1α. The interaction of VCP with both IRE1α and MTDH was dependent on ubiquitination. Moreover, MTDH stability was reduced in IRE1α-knockout cells. Hence, pharmacological manipulation of IRE1α–MTDH–VCP complex(es) might enable the treatment of MCL.

Metastatic breast cancer is a prime health concern and leading health burden across the globe. Previous efforts have shown that protein–protein interaction between Metadherin and Staphylococcal nuclease domaincontaining 1 (SND1) promotes initiation of breast cancer, progression, therapy resistance and metastasis. Therefore, small drug molecules that can interrupt the Metadherin and SND1 interaction may be ideal to suppress tumor growth, metastasis and increases chemotherapy sensitivity of triple negative breast cancer. Here, in this study, structure based virtual screening was conducted against the reported active site of SND1 enzyme, which revealed three promising lead molecules from Asinex library. These compounds were; BAS_00381028, BAS_00327287, and BAS_01293454 with binding energy score −10.25 kcal/mol, −9.65 kcal/mol and −9.32 kcal/mol, respectively. Compared to control (5-chloro-2-methoxy-N-([1,2,4]triazolo[1,5-a]pyridin-8-yl)benzene-1-sulfonamide) the lead molecules showed robust hydrophilic and hydrophobic interactions with the enzyme and revealed stable docked conformation in molecular dynamics simulation. During the simulation time, the compounds reported stable dynamics with no obvious fluctuation in binding mode and interactions noticed. The mean root mean square deviation (RMSD) of BAS_00381028, BAS_00327287, and BAS_01293454 complexes were 1.87 Å, 1.75 Å, 1.34 Å, respectively. Furthermore, the MM/GBSA analysis was conduction on the simulation trajectories of complexes that unveiled binding energy score of −19.25 kcal/mol, −27.03 kcal/mol, −34.6 kcal/mol and −29.61 kcal/mol for control, BAS_00381028, BAS_00327287, and BAS_01293454, respectively. In MM/PBSA, the binding energy value of for control, BAS_00381028, BAS_00327287, and BAS_01293454 was −20.45 kcal/mol, −27.89 kcal/mol, −36.41 kcal/mol and –32.01 kcal/mol, respectively. Additionally, the compounds were classified as druglike and have favorable pharmacokinetic properties. The compounds were predicted as promising leads and might be used in experimental investigation to study their anti-SND1 activity.

Background and purpose: Long non-coding RNA small nucleolar RNA host gene 5 (lncRNA SNHG5) plays a cancer-promoting role in many cancers, however its effect on colorectal cancer (CRC) and its regulatory mechanism are not clear. This study aimed to explore the mechanism of lncRNA SNHG5/miR-26a-5p/metadherin (MTDH) signal axis promoting metastasis of CRC. Methods: The data of The Cancer Genome Atlas (TCGA) database was analyzed, the abnormal expression of lncRNA in CRC was explored and analyzed the survival. Samples of CRC, paracancerous tissues and complete clinical data of patients who underwent surgical resection from October 2012 to October 2016 were collected. The expression levels of SNHG5 and miR-26a-5p in lncRNA were detected by real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR), and the expression level of MTDH was detected by immunohistochemistry. The relationship between the relative expression level of lncRNA SNHG5 in CRC and clinicopathological features and survival time was analyzed. The effects of lncRNA SNHG5 on the proliferation, migration and invasion of CRC cells were detected by cell counting kit-8 (CCK-8), clone formation, scratching assays, transwell test and in vivo xenotransplantation. The relationship between CRC cell metastasis, the expression level of epithelial-mesenchymal transition related molecules and lncRNA SNHG5 expression level by Western blot and immunohistochemical detection were explored. The physical interaction between SNHG5 and miR-26a-5p, MTDH and miR-26a-5p was studied by RNA pull-down test, double luciferase reporter gene detection and RNA co-immunoprecipitation. The functional relationship among the three was verified by CCK-8, EdU and transwell experiments. The effect of SNHG5, miR-26a-5p and MTDH expression on migration and invasion related molecules was analyzed by Western blot. Results: The results of TCGA database analysis showed that lncRNA SNHG5 was significantly upregulated in CRC. The results of RTFQ-PCR and immunohistochemistry showed that the levels of lncRNA SNHG5 and MTDH in CRC tissues were significantly upregulated (P＜0.05), the level of miR-26a-5p was decreased (P＜0.05), and the level of MTDH in samples with high expression of SNHG5 was also increased. The expression of lncRNA SNHG5 in CRC tissues with serosa and extraserosal invasion, distant metastasis, lymph node metastasis and TNM stage Ⅲ was significantly higher compared with subserosal invasion, no distant metastasis and lymph node metastasis and TNM stage Ⅰ-Ⅱ (P＜0.05). The results of survival analysis showed that the high expression of lncRNA SNHG5 was significantly correlated with overall survival rate (P＜0.05). Overexpression of lncRNA SNHG5 could enhance the proliferation, clone formation, migration and invasion of CRC cells, promote the growth and lung metastasis of transplanted tumor, increase the relative expression level of Ki-67 proliferation index and vimentin (P＜0.05), and decrease the relative expression level of E-cadherin (P＜0.05). However, the development of CRC cells was inhibited after inhibition of lncRNA SNHG5 expression. RNA pull-down test, double luciferase reporter gene detection and RNA co-immunoprecipitation confirmed the physical interaction between SNHG5 and miR-26a-5p, MTDH and miR-26a-5p. Upregulation of miR-26a-5p or downregulation of MTDH expression in lncRNA SNHG5 overexpressed cells partially reversed the effects of lncRNA SNHG5 on proliferation, migration, invasion and expression of related molecules in CRC cells. Conclusion: LncRNA SNHG5 is upregulated in CRC tissues and cells, and its high expression is related to tumor progression and poor survival. It can be used as a molecular sponge of miR-26a-5p to regulate the expression of MTDH to promote the proliferation and metastasis of SW620 cells. [ABSTRACT FROM AUTHOR]

Inflammatory breast cancer (IBC) is one of the most lethal subtypes of breast cancer (BC), accounting for approximately 1–5% of all cases of BC. Challenges in IBC include accurate and early diagnosis and the development of effective targeted therapies. Our previous studies identified the overexpression of metadherin (MTDH) in the plasma membrane of IBC cells, further confirmed in patient tissues. MTDH has been found to play a role in signaling pathways related to cancer. However, its mechanism of action in the progression of IBC remains unknown. To evaluate the function of MTDH, SUM-149 and SUM-190 IBC cells were edited with CRISPR/Cas9 vectors for in vitro characterization studies and used in mouse IBC xenografts. Our results demonstrate that the absence of MTDH significantly reduces IBC cell migration, proliferation, tumor spheroid formation, and the expression of NF-κB and STAT3 signaling molecules, which are crucial oncogenic pathways in IBC. Furthermore, IBC xenografts showed significant differences in tumor growth patterns, and lung tissue revealed epithelial-like cells in 43% of wild-type (WT) compared to 29% of CRISPR xenografts. Our study emphasizes the role of MTDH as a potential therapeutic target for the progression of IBC. [ABSTRACT FROM AUTHOR]

Previous studies have proved that zingerone was a therapeutic agent for many tumors. Metadherin (MTDH) acts as an oncogene and is involved in tumorigenesis. The purpose of this study was to explore the underlying mechanism of zingerone that regulates MTDH to affect hepatocellular carcinoma (HCC) progression. CCK-8 assay was performed to detect HCC cell proliferation. The invasion and migration abilities of HCC cells were evaluated using Transwell assay. The mRNA and protein levels in cells and tissues were measured using qRT-PCR and Western blot assays. Moreover, we established the HCC xenografts nude mice to evaluate the effect of zingerone on tumor growth. We found that zingerone treatment significantly inhibited HCC cell malignant phenotype and tumor growth. Moreover, MTDH was highly expressed in HCC tissues and cell lines and was positively associated with poor overall survival of patients with HCC. Knockdown of MTDH notably suppressed the proliferation, invasion, and migration capacities of HCC cells. Mechanistically, inhibition of MTDH by zingerone impeded the malignant biological behavior of HCC cells by inactivating the PI3K/Akt pathway. These results suggested that zingerone served as an effective therapeutic agent in HCC via blocking the MTDH-mediated PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]

Metadherin (MTDH), initially discovered in primary astrocytes of the human fetus through rapid subtraction hybridization and labeled as astrocyte elevated gene-1, represents a widely recognized oncogene present in multiple types of cancers. However, the role of MTDH in different types of cancer remains unclear. To address this, a comprehensive analysis of MTDH across various types of cancers was conducted by utilizing multiple databases such as The Cancer Genome Atlas. The present analysis discovered that MTDH exhibits differential expression in different types of cancer and is associated with important factors including tumor mutational burden and microsatellite instability. These findings highlighted the significance of MTDH in the tumor microenvironment and its involvement in the development of immune cells in specific cancers. Furthermore, the results of the present study indicated that the expression of MTDH is strongly correlated with clinical prognosis, mutations and immune cell infiltration. MTDH could serve as a potential indicator of patient prognosis and potentially play a role in modulating the immune system. Given its potential as a novel immunological checkpoint, MTDH may be a viable target for tumor immunotherapy. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) have been associated with a number of human malignancies, including breast cancer (BC). However, the expression, biological function and fundamental underlying mechanism of miR-217-5p in BC remain unclear. Therefore, in the present study, the expression levels of miR-217-5p and metadherin (MTDH) were examined in BC tissues and BC cell lines using reverse transcription-quantitative PCR. Cell Counting Kit-8 assays, cell proliferation, wound healing assays, Transwell assays and western blotting were used to examine the effects of miR-217-5p on cell proliferation, migration, the epithelial-mesenchymal transition (EMT) and NF-κB signaling pathway expression. The direct relationship between miR-217-5p and MTDH was assessed using a dual-luciferase reporter assay. The results demonstrated that significantly reduced expression levels of miR-217-5p but significantly increased mRNA expression levels of MTDH were observed in BC tissues from 35 patients with BC compared with non-tumor breast tissues. Furthermore, BC cell lines SK-BR3 and BT549 expressed miR-217-5p at markedly lower levels and MTDH at markedly higher levels compared with the breast epithelial MCF10A cell line. miR-217-5p overexpression significantly inhibited cell proliferation, invasion and migration and suppressed the EMT in BC cells. miR-217-5p overexpression also inhibited the NF-κB signaling pathway by markedly decreasing p65 mRNA and protein expression levels but significantly increasing IκBα expression levels. Furthermore, miR-217-5p knockdown markedly increased MTDH mRNA and protein expression levels. The expression levels of miR-217-5p were negatively correlated with those of MTDH in BC tissues. These results suggested that restoration of MTDH expression levels could potentially attenuate the inhibitory effects of miR-217-5p overexpression on BC cell proliferation. Therefore, in conclusion miR-217-5p overexpression may inhibit cell migration, invasion, the EMT and NF-κB signaling pathway in BC via targeting of MTDH. miR-217-5p may serve as an important potential target in BC therapy. [ABSTRACT FROM AUTHOR]

Inflammatory breast cancer (IBC) is one of the most lethal subtypes of breast cancer (BC), accounting for approximately 1–5% of all cases of BC. Challenges in IBC include accurate and early diagnosis and the development of effective targeted therapies. Our previous studies identified the overexpression of metadherin (MTDH) in the plasma membrane of IBC cells, further confirmed in patient tissues. MTDH has been found to play a role in signaling pathways related to cancer. However, its mechanism of action in the progression of IBC remains unknown. To evaluate the function of MTDH, SUM-149 and SUM-190 IBC cells were edited with CRISPR/Cas9 vectors for in vitro characterization studies and used in mouse IBC xenografts. Our results demonstrate that the absence of MTDH significantly reduces IBC cell migration, proliferation, tumor spheroid formation, and the expression of NF-κB and STAT3 signaling molecules, which are crucial oncogenic pathways in IBC. Furthermore, IBC xenografts showed significant differences in tumor growth patterns, and lung tissue revealed epithelial-like cells in 43% of wild-type (WT) compared to 29% of CRISPR xenografts. Our study emphasizes the role of MTDH as a potential therapeutic target for the progression of IBC.

Objectives: This study aimed to evaluate the prognostic significance and relationship of miR-497 and metadherin to hepatocellular carcinoma (HCC) tumor characteristics and patients’ survival. Methods: This study enrolled 120 (60 HCC patients and 60 healthy) subjects. Serum miR-497 and metadherin mRNA relative expression were analyzed by real-time quantitative reverse transcription polymerase chain reaction. The overall survival (OS) of HCC patients was assessed using the Kaplan–Meier curve and log-rank test. Results: Serum miR-497 showed statistically significant downregulation in HCC patients compared to controls (p < 0.001). Serum metadherin mRNA relative expression was significantly upregulated in HCC patients compared to controls (p < 0.001). Both serum miR-497 and metadherin mRNA expression were significantly associated with the number of tumor foci (p = 0.028 and 0.001, respectively), tumor size (p = 0.022 and <0.001, respectively), nodal metastasis (p = 0.003 and 0.003, respectively), distant metastasis (p = 0.003 and 0.003, respectively), vascular invasion (p = 0.040 and <0.001, respectively), and BCLC staging (p = 0.043 and 0.004, respectively). The overall survival was lower in patients with low miR-497 expression (p = 0.046) and in patients with high metadherin expression (p < 0.001). Conclusions: The expression levels of miR-497 showed downregulation in HCC patients, but metadherin expression showed upregulation. Both markers were inversely related and closely correlated with tumor characteristics and patients’ survival [ABSTRACT FROM AUTHOR]

Di Feng,1 Xiaoyu Yu,1 Xing Tian,2 Hongxue Meng,1 Yang Jiang,1 HongTao Song,1 WenQi Li,1 HaoCheng Zhang,3 Jingshu Geng1 1Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, People’s Republic of China; 2Department of Microbiology and Center of Infectious Disease, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, People’s Republic of China; 3Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150070, People’s Republic of ChinaCorrespondence: Jingshu GengDepartment of Pathology, Harbin Medical University Cancer Hospital, 7th Floor, Outpatient Building, Harbin, Heilongjiang 150081, People’s Republic of ChinaEmail gengjingshu@yeah.netPurpose: Metadherin (MTDH), as an oncogene, is associated with metastasis and poor prognosis. This study investigated MTDH expressions and development of gastric cancer (GC) cell phenotypes and the contribution of MTDH to epithelial–mesenchymal transition (EMT).Patients and methods: MTDH expression was assayed in human GC cell lines and tumor tissue from 92 GC patients. Functional experiments were performed to characterize MTDH activity. Expressions of EMT-related proteins (vimentin and E-cadherin), phosphorylated β-catenin and β-catenin were assayed by immunohistochemistry, Western blotting, immunofluorescence, and co-immunoprecipitation, respectively.Results: MTDH expressions were higher in GC tissue than that in gastric mucosa from the same patient. MTDH overexpression was correlated with metastasis and enhanced malignant GC phenotypes, i.e., proliferation, migration, invasiveness, and chemoresistance. MTDH overexpression was associated with expressions of vimentin, E-cadherin and cancer stem-cell biomarkers including CD44, CD133, and Oct4. MTDH complexed with β-catenin and decreased phosphorylated β-catenin levels to facilitate β-catenin translocation into the nucleus and expressions of downstream genes.Conclusion: MTDH overexpression in GC cells is associated with EMT and development of cancer stem cell malignant phenotypes and affects the subcellular translocation of β-catenin. The results warrant investigation of the prognostic value of MTDH in GC and as a therapeutic target.Keywords: metadherin, gastric cancer, CD44, β-catenin, cancer stem cells

Tong Li,1 Yunpeng Li,2 Hongyan Sun11Department of General Surgery, The Fourth People’s Hospital of Jinan, Jinan, Shandong 250031, People’s Republic of China; 2Department of General Surgery, Ningjin County People’s Hospital, Ningjin, Shandong 253400, People’s Republic of ChinaBackground: 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.Keywords: breast cancer, microRNA-876-5p, metadherin, long intergenic non-protein-coding RNA 707, therapeutic target

Lunqiang Zhang,1 Chenglong Li,1 Lijun Cao,2 Hui Li,2 Haiding Zou,2 Hongqin Li,2 Haiping Pei11Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Hunan 410008, People’s Republic of China; 2Department of Anesthesiology, The Second Xiangya Hospital of Central South University, Hunan 410011, People’s Republic of ChinaBackground: 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.Keywords: microRNA-877, colorectal cancer, metadherin, PTEN/Akt pathway

Objective To explore the effect of metadherin (MTDH) on cell proliferation and paclitaxel resistance in nasopharyngeal carcinoma (NPC) patients. Methods The expression of MTDH was upregulated and inhibited by lentivirus-mediated MTDH cDNA and MTDH-shRNA in NPC cells, respectively. Cell proliferation, cell cycles and apoptosis were examined by CCK-8 and flow cytometry. The IC30, IC50, IC70 value of paclitaxel in NPC cells were obtained by CCK-8 assay. Then, the survival rates of MTDH overexpression cells and MTDH silence cells, stimulated with paclitaxel at IC30, IC50 and IC70, were evaluated using CCK-8 assay. Results MTDH overexpression enhanced the proliferation abilities of 5-8F and HNE-1 cells, while MTDH silence inhibited the proliferation abilities and greatly increased cells in G1 phase. The apoptosis was decreased by MTDH overexpression, and promoted by MTDH silence. MTDH overexpression induced paclitaxel resistance. Compared with control group, survival rate of MTDH overexpression cells in the presence of paclitaxel at IC70 and IC50 was increased. On the contrary, MTDH silence sensitized NPC cells to paclitaxel. The survival rate of MTDH silence cells in the presence of paclitaxel at IC50 and IC30 was decreased. Conclusion MTDH plays an important role in promoting NPC cell proliferation, and the high expression of MTDH could induce paclitaxel resistance in NPC cells.

Zhang L, Li C, Cao L, et al. Cancer Manag Res. 2019;11:2769–2781. The Editor and Publisher of Cancer Management and Research wish to retract the published article. Concerns were raised over alleged image duplication in Figures 2D, 3B and 6E with similar images from unrelated articles, specifically: Figure 2D, panel HCT-116 miR-877 mimics appears to have been duplicated with a similar image in Figure 2G from Ji et al, 2017 (https://doi.org/10.3892/mmr.2017.7332) and Figure 2D from Hu et al, 2018 (https://doi.org/10.3727/096504018X15154112497142). Figure 3B, panel HCT-116 miR-877 mimics appears to have been duplicated with a similar image in Figure 2C from Zhou et al, 2019 (DOI: 10.3892/etm.2019.7676). Figure 6E, panel SW-480 miR-877 mimics+pcDNA3.1 appears to have been duplicated with a similar image in Figure 5C from Zhou et al, (DOI: 10.3892/etm.2019.7676). The authors responded to our queries but were unable to provide a satisfactory explanation for the alleged duplication and could not provide satisfactory original data for their study. The Editor advised for the article to be retracted. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Osteosarcoma is the most common primary malignant tumor, especially in children and adolescents. Circular RNAs (circRNAs) are found to play roles in the progression of osteosarcoma. However, the exact functions of circRNAs in osteosarcoma development still need to be clarified. We obtained differentially expressed circRNAs and miRNAs from a GSE99671 data set (GEO database). The gene co-expression network of ceRNAs and osteosarcoma-related genes was analyzed using the STRING database. qRT-PCR was used to detect the expression of circ-03955 and miR-3662. Transwell assays and flow cytometry were performed to detect phenotypic changes in cell function. A xenograft tumor model was established using BALB/c nude mice. Dual luciferase activity and RNA immunoprecipitation assays were performed to assess the relationship between circ-03955, miR-3662, and metadherin (MTDH). Immunohistochemistry, immunofluorescence, and Western blotting were used to assess protein expression levels. Circ-03955 was significantly upregulated, and miR-3662 was downregulated in osteosarcoma. Circ-03955 silencing inhibited the growth and metastasis of osteosarcoma. Mechanism analysis revealed that circ-03955 could bind to miR-3662, and the latter could target MTDH, leading to its suppressed expression and facilitating epithelial-mesenchymal transition (EMT). All these findings demonstrate that the presence of circ-03955 promotes EMT in osteosarcoma by acting as miR-3662 sponge-mediated MTDH expression.

Wuguo Tian, Shuai Hao, Bo Gao, Yan Jiang, Xiaohua Zhang, Shu Zhang, Lingji Guo, Jianjie Zhao, Gang Zhang, Yi Chen, Zhirong Li, Donglin Luo Department of Breast, Thyroid Surgery, Research Institute of Surgery, Daping Hospital, Army Military Medical University, Chongqing 400042, China Objective: Lobaplatin shows antitumor activity against a wide range of tumors, including metastatic breast cancer (BCa). The overexpression of metadherin (MTDH) is associated with poor prognosis of BCa patients. This study was designed to investigate the effect of lobaplatin on MCF-7 cell proliferation and its association with MTDH expression.Patients and methods: Clinical treatment for BCa using lobaplatin, in combination with other general chemotherapy drugs, was administered to 32 BCa patients. The safety, effectiveness, and prognosis in lobaplatin-treated BCa patients were compared with those in controls (n=32). In vitro experiments were performed in MCF-7 cells to investigate the effect of lobaplatin on cell proliferation, apoptosis, and MTDH expression.Results: We found the intraoperative local chemotherapy using lobaplatin was safe and effective for BCa treatment, in comparison with the patients administered general chemotherapy drugs. Treatment of MCF-7 cell cultures with lobaplatin significantly reduced cell proliferation and increased cell apoptotic percentage. The expression of MTDH and Bcl-2 was inhibited by lobaplatin and that of Bax was increased by lobaplatin. Moreover, we observed the inhibition of MTDH by shRNA reduced cell proliferation and enhanced cell apoptosis.Conclusion: Lobaplatin was a safe and effective adjuvant chemotherapy for BCa. The effect of lobaplatin on inhibiting MCF-7 cell proliferation and inducing cell apoptosis might be, as least in part, mediated by suppressing the expression of oncogene MTDH. Keywords: breast cancer, lobaplatin, proliferation, apoptosis, MTDH

Osteosarcoma is the most common primary malignant tumor, especially in children and adolescents. Circular RNAs (circRNAs) are found to play roles in the progression of osteosarcoma. However, the exact functions of circRNAs in osteosarcoma development still need to be clarified. We obtained differentially expressed circRNAs and miRNAs from a GSE99671 data set (GEO database). The gene co-expression network of ceRNAs and osteosarcoma-related genes was analyzed using the STRING database. qRT-PCR was used to detect the expression of circ-03955 and miR-3662. Transwell assays and flow cytometry were performed to detect phenotypic changes in cell function. A xenograft tumor model was established using BALB/c nude mice. Dual luciferase activity and RNA immunoprecipitation assays were performed to assess the relationship between circ-03955, miR-3662, and metadherin (MTDH). Immunohistochemistry, immunofluorescence, and Western blotting were used to assess protein expression levels. Circ-03955 was significantly upregulated, and miR-3662 was downregulated in osteosarcoma. Circ-03955 silencing inhibited the growth and metastasis of osteosarcoma. Mechanism analysis revealed that circ-03955 could bind to miR-3662, and the latter could target MTDH, leading to its suppressed expression and facilitating epithelial-mesenchymal transition (EMT). All these findings demonstrate that the presence of circ-03955 promotes EMT in osteosarcoma by acting as miR-3662 sponge-mediated MTDH expression. [ABSTRACT FROM AUTHOR]

Early diagnosis and treatment of colorectal cancer (CRC) are important for improving patients' survival. Metadherin is an oncogene that plays a pivotal role in carcinogenesis and can be suggested as a cancer biomarker. This study aimed to elucidate the efficacy of serum Metadherin mRNA expression as a potential non-invasive biomarker for early diagnosis of CRC in relation to other screening markers as carcinoembryonic antigen (CEA), carbohydrate antigen 19.9 (CA19.9) and Fecal occult blood (FOB) and also to assess its relationship with the tumor stage and survival rate. A convenience series of 86 CRC cases (group I) were recruited with 78 subjects as controls (group II). Serum Metadherin mRNA expression level was determined using reverse transcription polymerase chain reaction (RT-PCR). Serum Metadherin mRNA expression level was significantly elevated in CRC cases when compared with controls (P < 0.001). For CRC diagnosis; Receiver operator characteristic (ROC) analyses revealed that the diagnostic accuracy of serum Metadherin mRNA (AUC = 0.976) was significantly higher than other routine CRC screening markers as CEA, CA19.9 and FOB. The combined accuracy of these markers (AUC = 0.741) was increased when used with serum Metadherin mRNA (AUC = 0.820). High serum Metadherin mRNA expression was associated with poorly differentiated histological grade, advanced tumor stage and lower survival rate. AUC of Metadherin was 0.820 for differentiating advanced versus early tumor stages. Serum Metadherin mRNA expression is a useful non-invasive biomarker for CRC. It can be used for screening and early diagnosis of CRC and can increase the efficacy of other routine CRC screening markers when it is estimated in CRC patients with them. It is also associated with advanced tumor stage and a lower survival rate. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is the most aggressive gynecological cancer. Even with the advances in detection and therapeutics, it still remains clinically challenging and there is a pressing need to identify novel therapeutic strategies. In searching for rational molecular targets, we identified metadherin (MTDH), a multifunctional gene associated with several tumor types but previously unrecognized in OC. In this study, we found the MTDH is overexpressed in OC tissues. Through in vitro assays with overexpression cells, we characterized the role of MTDH. We confirmed MTDH stable overexpression significantly increased the expression of TNF-α, IL-6, IL-8, IL-10, and IL-1β. Interestingly, NF-kappa-B (NF-κB) and MTDH were found in a feed-forward loop motif. Thus, our findings support the notion that the MTDH and NF-κB signaling network contributes to OC traits. MTDH represents a new OC-associated gene that can contribute to insights of OC biology and suggests other treatment strategies. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to evaluate the prognostic significance and relationship of miR-497 and metadherin to hepatocellular carcinoma (HCC) tumor characteristics and patients’ survival. Methods: This study enrolled 120 (60 HCC patients and 60 healthy) subjects. Serum miR-497 and metadherin mRNA relative expression were analyzed by real-time quantitative reverse transcription polymerase chain reaction. The overall survival (OS) of HCC patients was assessed using the Kaplan–Meier curve and log-rank test. Results: Serum miR-497 showed statistically significant downregulation in HCC patients compared to controls (p < 0.001). Serum metadherin mRNA relative expression was significantly upregulated in HCC patients compared to controls (p < 0.001). Both serum miR-497 and metadherin mRNA expression were significantly associated with the number of tumor foci (p = 0.028 and 0.001, respectively), tumor size (p = 0.022 and p = 0.003 and 0.003, respectively), distant metastasis (p = 0.003 and 0.003, respectively), vascular invasion (p = 0.040 and p = 0.043 and 0.004, respectively). The overall survival was lower in patients with low miR-497 expression (p = 0.046) and in patients with high metadherin expression (p < 0.001). Conclusions: The expression levels of miR-497 showed downregulation in HCC patients, but metadherin expression showed upregulation. Both markers were inversely related and closely correlated with tumor characteristics and patients’ survival.

Altered expression of many genes and proteins is essential for cancer development and progression. Recently, the affected expression of metadherin (MTDH), also known as AEG-1 (Astrocyte Elevated Gene 1) and Lyric, has been implicated in various aspects of cancer progression and metastasis. Elevated expression of MTDH/AEG-1 has been reported in many cancers including breast, prostate, liver, and esophageal cancers, whereas its expression is low or absent in non-malignant tissues. These expression studies suggest that MTDH may represent a potential tumor associated antigen. MTDH also regulates multiple signaling pathways including PI3K/Akt, NF-κB, Wnt/β-catenin, and MAPK which cooperate to promote the tumorigenic and metastatic potential of transformed cells. Several microRNA have also been found to be associated with the increased MTDH expression in different cancers. Increased MTDH levels were linked to the tumor chemoresistance making it an attractive novel therapeutic target. In this review, we summarize data on MTDH function in various cancers.

Background: Metadherin ( MTDH ) is a key oncogene in most cancer types, including hepatocellular carcinoma (HCC). Notably, MTDH does not affect the stemness pheno-type or immune infiltration of HCC., Aim: To explore the role of MTDH on stemness and immune infiltration in HCC ., Methods: MTDH expression in HCC tissues was detected using TCGA and GEO databases. Immunohistochemistry was used to analyze the tissue samples. MTDH was stably knocked down or overexpressed by lentiviral transfection in the two HCC cell lines. The invasion and migration abilities of HCC cells were evaluated using Matrigel invasion and wound healing assays. Next, we obtained liver cancer stem cells from the spheroids by culturing them in a serum-free medium. Gene expression was determined by western blotting and quantitative reverse transcri-ption PCR. Flow cytometry, immunofluorescence, and tumor sphere formation assays were used to characterize stem-like cells. The effects of MTDH inhibition on tumor growth were evaluated in vivo . The correlation of MTDH with immune cells, immunomodulators, and chemokines was analyzed using ssGSEA and TISIDB databases., Results: HCC tissues expressed higher levels of MTDH than normal liver tissues. High MTDH expression was associated with a poor prognosis. HCC cells overexpressing MTDH exhibited stronger invasion and migration abilities, exhibited a stem cell-like phenotype, and formed spheres; however, MTDH inhibition attenuated these effects. MTDH inhibition suppressed HCC progression and CD133 expression in vivo . MTDH was positively correlated with immature dendritic, T helper 2 cells, central memory CD8 + T, memory B, activated dendritic, natural killer (NK) T, NK, activated CD4 + T, and central memory CD4 + T cells. MTDH was negatively correlated with activated CD8 + T cells, eosinophils, activated B cells, monocytes, macrophages, and mast cells. A positive correlation was observed between the MTDH level and CXCL2 expression, whereas a negative correlation was observed between the MTDH level and CX3CL1 and CXCL12 expression., Conclusion: High levels of MTDH expression in patients with HCC are associated with poor prognosis, promoting tumor stemness, immune infiltration, and HCC progression., Competing Interests: Conflict-of-interest statement: No conflict of interest has been declared by any of the authors., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

In perinatal medicine, intrauterine growth restriction (IUGR) is one of the greatest challenges. The etiology of IUGR is multifactorial, but most cases are thought to arise from placental insufficiency. However, identifying the placental cause of IUGR can be difficult due to numerous confounding factors. Selective IUGR (sIUGR) would be a good model to investigate how impaired placentation affects fetal development, as the growth discordance between monochorionic twins cannot be explained by confounding genetic or maternal factors. Herein, we constructed and analyzed the placental proteomic profiles of IUGR twins and normal cotwins. Specifically, we identified a total of 5481 proteins, of which 233 were differentially expressed (57 up-regulated and 176 down-regulated) in IUGR twins. Bioinformatics analysis indicates that these differentially expressed proteins (DEPs) are mainly associated with cardiovascular system development and function, organismal survival, and organismal development. Notably, 34 DEPs are significantly enriched in angiogenesis, and diminished placental angiogenesis in IUGR twins has been further elaborately confirmed. Moreover, we found decreased expression of metadherin (MTDH) in the placentas of IUGR twins and demonstrated that MTDH contributes to placental angiogenesis and fetal growth in vitro. Collectively, our findings reveal the comprehensive proteomic signatures of placentas for sIUGR twins, and the DEPs identified may provide in-depth insights into the pathogenesis of placental dysfunction and subsequent impaired fetal growth., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Dysregulation of microRNA-618 (miR-618) has been observed in multiple types of human cancer. However, whether miR-618 is implicated in osteosarcoma (OS) initiation and progression is still unclear. Hence, we measured the expression of miR-618 in OS tissues and cell lines. In addition, the roles of miR-618 and the mechanisms underlying its activities in OS cells were examined. Methods: The expression status of miR-618 in OS was analyzed by reverse-transcription quantitative PCR. The regulatory roles of miR-618 overexpression in OS were explored by the Cell Counting Kit-8 assay, flow-cytometric analysis, Transwell cell migration and invasion assays, and a tumor xenograft experiment. Results: The results revealed that the expression of miR-618 was notably lower in OS tissues and cell lines, and that the low miR-618 expression significantly correlated with the clinical stage and distant metastasis among patients with OS. Exogenous miR-618 expression significantly suppressed OS cell proliferation, migration, and invasion and induced apoptosis in vitro as well as slowed tumor growth in vivo. Mechanism investigation indicated that metadherin (MTDH) is a direct target gene of miR-618 in OS cells. A knockdown of MTDH mimicked the tumor-suppressive effects of miR-618 upregulation on OS cells. Notably, resumption of MTDH expression attenuated the miR-618–mediated reduction in OS cell growth and metastasis in vitro. In addition, miR-618 overexpression reduced the PTEN–AKT pathway output in OS cells both in vitro and in vivo through downregulation of MTDH. Conclusion: To the best of our knowledge, this is the first study to show that miR-618 exerts crucial tumor-suppressive actions in OS pathogenesis by directly targeting MTDH mRNA and reducing PTEN–AKT pathway output. These results will help to elucidate the functions of miR-618 in OS and suggest that this miRNA may be investigated as a therapeutic target in this disease. [ABSTRACT FROM AUTHOR]

Purpose: Several microRNAs (miRNAs) that are aberrantly expressed in glioblastoma multiforme (GBM) play a significant role in GBM formation and progression. The expression profile and functions of miR-559 in GBM remain unclear. Here, we quantified the expression and investigated the involvement of miR-559 in the oncogenicity of GBM cells in vitro and in vivo. Material and methods: Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) was carried out to determine miR-559 expression in GBM tissues and cell lines. A series of functional assays was performed to evaluate the effects of miR-559 overexpression on GBM cell proliferation, apoptosis, migration, and invasion in vitro and on GBM tumor growth in vivo. The regulatory mechanisms of miR-559 action in GBM cells were then explored. Results: The expression of miR‑559 was lower in GBM tissues and cell lines and significantly correlated with the Karnofsky performance score and tumor size among patients with GBM. Exogenous miR‑559 expression inhibited GBM cell proliferation, migration, and invasion and promoted apoptosis. MiR-559 overexpression decreased tumor growth in vivo. Mechanistic experiments confirmed metadherin (MTDH) as a direct target gene of miR-559 in GBM. Silencing of MTDH induced effects similar to those of miR-559 upregulation in GBM cells, whereas MTDH expression restoration attenuated the antitumor effects of miR‑559 in GBM cells. Protein kinase B (AKT) in the phosphatase and tensin homolog (PTEN)–AKT signaling pathway was found to be deactivated in GBM cells after upregulation of miR-559 both in vitro and in vivo. Conclusion: MiR-559 acts as a tumor suppressor in GBM cells in vitro and in vivo, at least in part through the downregulation of MTDH and inhibition of AKT in the PTEN–AKT pathway. Therefore, targeting the miR-559–MTDH axis may be a promising therapeutic strategy for patients with GBM. [ABSTRACT FROM AUTHOR]

Altered expression of many genes and proteins is essential for cancer development and progression. Recently, the affected expression of metadherin (MTDH), also known as AEG-1 (Astrocyte Elevated Gene 1) and Lyric, has been implicated in various aspects of cancer progression and metastasis. Elevated expression of MTDH/AEG-1 has been reported in many cancers including breast, prostate, liver, and esophageal cancers, whereas its expression is low or absent in non-malignant tissues. These expression studies suggest that MTDH may represent a potential tumor associated antigen. MTDH also regulates multiple signaling pathways including PI3K/Akt, NF-κB, Wnt/β-catenin, and MAPK which cooperate to promote the tumorigenic and metastatic potential of transformed cells. Several microRNA have also been found to be associated with the increased MTDH expression in different cancers. Increased MTDH levels were linked to the tumor chemoresistance making it an attractive novel therapeutic target. In this review, we summarize data on MTDH function in various cancers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To analyze the effect of microRNA‐22 on autophagy and proliferation and to investigate the underlying molecular mechanism of osteosarcoma cell chemotherapy sensitivity. Methods: MG‐63 cells were divided into four groups, including a control group, a negative control (NC) group, a cisplatin group, and a cisplatin + miR‐22 group. Proliferation of MG‐63 cells that had been treated with cisplatin and transfected with miR‐22 mimics was determined using MTT assay and colony formation assay. We assessed the degree of autophagy using flow cytometry through cellular staining of the autophagy lysosomal marker monodansylcadaverine (MDC). The effect of microRNA‐22 on autophagy was observed along with the expression levels of Beclin1, LC3, metadherin (MTDH) and ATG5 by western blot and quantitative reverse transcription polymerase chain reaction (qRT‐PCR). Luciferase reporter assay revealed the targeted binding site between miR‐22 and the 3′‐untranslated region (3′‐UTR) of MTDH mRNA. Western blot and qRT‐PCR were used to explore the level of MTDH in the control group, the NC group, the cisplatin group, and the miR‐22 group for 6, 12, and 24 h. Results: In the in vitro study, the MTT results indicated that the MG‐63 cells with overexpression of miR‐22 exhibited a significant decline in the proliferation capacity compared with the control group (0.513 ± 0.001, P < 0.0005). Similar to the MTT results, MG‐63 cells that were transfected with miR‐22 mimic (101.0 ± 10.58) formed fewer colonies compared with the cisplatin group (129.7 ± 4.163). MDC staining revealed that miR‐22‐overexpressing osteosarcoma (OS) cells treated with cisplatin showed a significant decrease in the expression of autophagy (7.747 ± 0.117, P < 0.0001). Our data revealed that miR‐22 could regulate not only autophagy but also proliferation in the chemosensitivity of osteosarcoma cells. We found that miR‐22 sensitized osteosarcoma cells to cisplatin treatment by regulating autophagy‐related genes. In addition, Luciferase Reporter Assay revealed that miR‐22 negatively regulated autophagy through direct targeting of MTDH. We performed western blot analysis to detect the MTDH expression level. The results revealed that the overexpression of miR‐22 obviously decreased the expression of MTDH (1.081 ± 0.023, P < 0.001). Conclusion: Inhibition of miR‐22 ameliorated the anticancer drug‐induced cell proliferation decrease in osteosarcoma cells. MTDH was identified as the miR‐22 target in OS cells and MTDH‐triggered autophagy played a key function in the miR‐22‐associated chemotherapy sensitivity. [ABSTRACT FROM AUTHOR]

Numerous microRNAs (miRNAs) are dysregulated in tongue squamous cell carcinoma (TSCC), and their dysregulation has been demonstrated to have a strong correlation with TSCC progression via regulation of their targets. Therefore, miRNAs have potential use in the diagnosis and treatment of patients with TSCC. In the present study, miRNA-758 (miR-758) expression in TSCC tissues and cell lines was detected through reverse transcription-quantitative polymerase chain reaction, and the effects of miR-758 on TSCC cell proliferation and invasion were investigated by using Cell Counting kit-8 and Transwell invasion assays. A luciferase reporter assay was performed to determine the target interaction between miR-758 and metadherin (MTDH) in TSCC cells. The results revealed that miR-758 was downregulated in TSCC tissues and cell lines. miR-758 overexpression restricted the proliferation and invasion of TSCC cells. Additionally, MTDH was verified as a direct target gene of miR-758 in TSCC cells. Furthermore, MTDH was observed to be upregulated in TSCC tissues, and the upregulation of MTDH was inversely correlated with miR-758 expression. Moreover, restored MTDH expression significantly counteracted the suppressive effects of miR-758 overexpression on TSCC cells. These results suggested that miR-758 may prevent TSCC progression and development by directly targeting MTDH, thereby providing evidence that miR-758 is a novel therapeutic target for the treatment of patients with TSCC. [ABSTRACT FROM AUTHOR]

Metastatic breast cancer is a prime health concern and leading health burden across the globe. Previous efforts have shown that protein–protein interaction between Metadherin and Staphylococcal nuclease domaincontaining 1 (SND1) promotes initiation of breast cancer, progression, therapy resistance and metastasis. Therefore, small drug molecules that can interrupt the Metadherin and SND1 interaction may be ideal to suppress tumor growth, metastasis and increases chemotherapy sensitivity of triple negative breast cancer. Here, in this study, structure based virtual screening was conducted against the reported active site of SND1 enzyme, which revealed three promising lead molecules from Asinex library. These compounds were; BAS_00381028, BAS_00327287, and BAS_01293454 with binding energy score −10.25 kcal/mol, −9.65 kcal/mol and −9.32 kcal/mol, respectively. Compared to control (5-chloro-2-methoxy-N-([1,2,4]triazolo[1,5-a]pyridin-8-yl)benzene-1-sulfonamide) the lead molecules showed robust hydrophilic and hydrophobic interactions with the enzyme and revealed stable docked conformation in molecular dynamics simulation. During the simulation time, the compounds reported stable dynamics with no obvious fluctuation in binding mode and interactions noticed. The mean root mean square deviation (RMSD) of BAS_00381028, BAS_00327287, and BAS_01293454 complexes were 1.87 Å, 1.75 Å, 1.34 Å, respectively. Furthermore, the MM/GBSA analysis was conduction on the simulation trajectories of complexes that unveiled binding energy score of −19.25 kcal/mol, −27.03 kcal/mol, −34.6 kcal/mol and −29.61 kcal/mol for control, BAS_00381028, BAS_00327287, and BAS_01293454, respectively. In MM/PBSA, the binding energy value of for control, BAS_00381028, BAS_00327287, and BAS_01293454 was −20.45 kcal/mol, −27.89 kcal/mol, −36.41 kcal/mol and –32.01 kcal/mol, respectively. Additionally, the compounds were classified as druglike and have favorable pharmacokinetic properties. The compounds were predicted as promising leads and might be used in experimental investigation to study their anti-SND1 activity. [ABSTRACT FROM AUTHOR]

The activation of oncogenes and the loss of tumor suppressor genes are believed toplay critical roles in the pathogenesis of human hepatocellular carcinoma (HCC). Metaherin (MTDH), also called astrocyte elevated gene-1 (AEG-1), is frequently amplified in a variety of cancers, but the roles of MTDH with regard to growth and apoptosis in HCC have not yet been studied. In the present study, we first analyzed the expression of MTDH in HCC samples. We found that MTDH protein levels are higher in most HCC cancerous tissues compared with their matched adjacent non-tumor tissues. Additionally, the MTDH mRNA was also higher in HCC tissues compared to their matched adjacent non-tumor tissues. Knockdown of the endogenous MTDH using small interfering RNA further showed that deficiency of MTDH suppressed cell growth and caused apoptosis in HCC cells. Knockdown MTDH promoted PTEN and p53 expression in HCC cells and inhibited AKT phosphorylation. Knockdown MTDH also inhibited tumor growth in vivo. All these results indicated that MTDH protein levels in most HCC tissues are higher than non-tumor tissues, and knockdown of MTDH inhibited growth and induced apoptosis in HCC cells through the activation of PTEN. Therefore, MTDH might be an effective targeted therapy gene for HCC.

Background: Metadherin (MTDH) has been known as an essential oncogene in carcinogenesis and tumor spread in several malignancies, via its effect on pathways of signal transduction. Objective: We aimed to evaluate the role of serum MTDH mRNA expression in the diagnosis of hepatocellular carcinoma (HCC) and to compare its expression levels with serum levels of Alpha-fetoprotein (AFP). Subjects & methods: A total of 150 subjects (90 HCC patients & 60 healthy volunteers) were enrolled in the current study. Serum MTDH mRNA relative expression was analyzed by Real Time PCR technique. Results: There was a significant statistical increase of serum MTDH mRNA expression in HCC group when compared to controls (P < 0.05). MTDH mRNA expression was significantly associated with clinicopathological data, advanced tumor stage and poor histological differentiation in HCC patients (p < 0.05). There was direct positive correlation between MTDH mRNA expression and serum AFP levels in HCC group (r = 0.445), P value = <0.05. ROC curve was used to verify the accuracy of MTDH mRNA expression and compare it with accuracy of serum AFP in HCC diagnosis; MTDH mRNA expression had higher accuracy (92%), sensitivity (91%) and specificity (93%) than AFP. Conclusion: MTDH mRNA is up-regulated in serum of HCC patients; MTDH may be considered as noninvasive biomarker for HCC diagnosis and it could replace serum AFP in HCC diagnosis as it had higher accuracy. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs/miRs) serve important roles in regulating gene expression by directly binding to the 3′-untranslated regions of target genes. Multiple miRNAs are dysregulated in retinoblastoma (RB) and their dysregulation is closely related to RB malignancy. Therefore, exploring the detailed roles of miRNAs in RB is valuable to facilitate the development of effective therapeutic targets for patients with this disease. miRNA-874-3p (miR-874) has been recently reported to be downregulated in several types of human cancer and serves an essential role in cancer progression. However, the expression pattern and detailed roles of miR-874 in RB, as well as the underlying molecular mechanisms in RB, have not been clearly elucidated. Therefore, this study detected miR-874 expression in RB tissues and cell lines. The biological roles of miR-874 in RB were determined and the underlying mechanisms of its actions in RB cells were also examined. This study revealed that miR-874 expression was aberrantly underexpressed in RB tissues and cell lines. However, returning miR-874 expression restricted the proliferative and invasive abilities of RB cells. In terms of the underlying mechanism, metadherin (MTDH) was validated as a direct target gene of miR-874 in RB cells. MTDH inhibition could imitate the inhibitory roles of miR-874 overexpression in RB cells. Furthermore, forced MTDH expression partially reversed the suppressive effects of miR-874 on RB cells. In conclusion, this study revealed that miR-874 may inhibit RB progression by directly targeting MTDH. Restoration of miR-874 expression may be a novel strategy for preventing the rapid growth and metastasis of RB cells. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are important regulators of a variety of biological processes and their dysregulation is closely related to cancer formation and progression. Therefore, examination of aberrantly expressed miRNAs in oral squamous cell carcinoma (OSCC) may provide important clues for the diagnosis and treatment of patients with OSCC. The aim of the present study was to determine miRNA (miR)-655-3p expression in OSCC tissues and cell lines, and to investigate the biological roles and mechanisms of miR-655-3p associated with OSCC. Data from the present study indicated that miR-655 expression was significantly downregulated in human OSCC tissues and cell lines. Overexpression of miR-655 attenuated cell proliferation and invasion in OSCC in vitro. Metadherin (MTDH) mRNA was predicted as a potential target of miR-655 by bioinformatics analysis, and this was confirmed by luciferase reporter assay, reverse transcription-quantitative polymerase chain reaction and western blot analysis. In OSCC tissues, MTDH was highly expressed and inversely correlated with miR-655 expression levels. MTDH overexpression reversed the inhibitory effects of miR-655 mimics in OSCC cells. Notably, the upregulation of miR-655 expression inhibited the activation of the phosphatase and tensin homolog (PTEN)/RAC-α serine/threonine-protein kinase (AKT) pathway in OSCC cells. Therefore, these results may provide the first evidence that miR-655 targets MTDH to inhibit proliferation and invasion of OSCC by inhibiting PTEN/AKT signaling. Thus, the restoration of miR-655 expression may be a novel therapeutic strategy for patients with OSCC. [ABSTRACT FROM AUTHOR]

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. CONCLUSION: 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. [ABSTRACT FROM AUTHOR]

Numerous microRNAs (miRNAs) are aberrantly expressed in glioma, and implicated in glioma occurrence and development. Therefore, the development of miRNAs as potential therapeutic targets for the treatment of patients with glioma has been proposed. miR‑379 has been shown to be aberrantly expressed in the progression of malignant tumours. However, the expression, biological functions and mechanism of miR‑379 in glioma are yet to be fully understood. Hence, the present study aimed to detect miR‑379 expression, investigate its functional relevance and explore its associated molecular mechanism in glioma. In this study, miR‑379 expression was significantly downregulated in glioma tissues and cell lines. Enforced miR‑379 expression markedly suppressed the cell proliferation and invasion of glioma. Metadherin (MTDH) was identified as a direct target of miR‑379 in glioma. The miR‑379 expression and MTDH mRNA levels exhibited an inverse association in glioma tissues. The restoration of the MTDH expression partially rescued the inhibitory effects of miR‑379 overexpression on glioma cell proliferation and invasion, and the upregulation of miR‑379 inhibited the activation of phosphatase and tensin homolog (PTEN)/AKT serine/threonine kinase (AKT) signaling pathway. Overall, these findings demonstrated that miR‑379 may play tumour‑suppressing roles in glioma through downregulation of MTDH and regulation of the PTEN/AKT signaling pathway, suggesting that miR‑379 might be a possible target for the treatment of patients with this malignancy. [ABSTRACT FROM AUTHOR]

Paclitaxel resistance is a challenge to the treatment of nasopharyngeal carcinoma (NPC). An acidic extracellular pH (pHe), a hallmark of solid tumors, is demonstrated to decrease the efficacy of chemotherapy. However, the precise function of acidic pHe in mediating chemotherapy in NPC remains unknown. In the present study, acidic pHe significantly decreased the cytotoxicity of paclitaxel in NPC cells. In addition, epithelial‑mesenchymal transition (EMT)‑like changes were observed in NPC cells cultured at acidic pHe. Metadherin (MTDH), a novel oncogene, is expressed in multiple types of solid tumor, and is associated with several malignant cell characteristics, including malignant cell transformation, proliferation, angiogenesis, chemoresistance, invasion and metastasis. In the present study, MTDH expression was increased in NPC cells that had been cultured at an acidic pHe. Furthermore, the silencing of MTDH expression reversed EMT molecular marker expression and sensitized NPC cells to paclitaxel. Taken together, the results of the present study provide evidence to support an association between acidic pHe‑induced paclitaxel resistance and MTDH‑mediated EMT in NPC cells. Thus, targeting MTDH may provide a novel strategy for overcoming chemoresistance in NPC therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Lung cancer is the third most frequent human malignant tumour and the leading cause of cancer-associated mortality worldwide. Emerging lines of evidence have demonstrated that microRNAs (miRNAs) are upregulated or downregulated in non-small cell lung cancer (NSCLC), and this phenomenon is involved in the regulation of various processes during tumorigenesis and progression, including tumour groWTh, apoptosis, cell invasion, and tumour metastasis. Therefore, understanding the molecular mechanism that associates abnormally expressed miRNAs with NSCLC formation and development may lead to the identification of novel diagnostic, and therapeutic targets for patients with NSCLC. miRNA-584 (miR-584) functions as a tumour suppressor in several types of cancer. However, the expression pattern, detailed biological function and underlying molecular mechanism of miR-584 in NSCLC remain unclear. Therefore, the present study detected the expression of miR-584 in NSCLC, investigated its role in NSCLC cells and determined its underlying molecular mechanism. In the current study, it was demonstrated that miR-584 was downregulated in NSCLC tissues and cell lines. Low miR-584 expression was correlated with tumour size, tumour node metastasis stage and distant metastasis. Overexpression of miR-584 inhibited cell proliferation and invasion in NSCLC. Additionally, metadherin was identified as a direct target gene of miR-584 in NSCLC as confirmed by a series of experiments. Moreover, upregulation of miR-584 was involved in the regulation of the phosphatase and tensin homolog/Akt serine/threonine kinase signalling pathway in NSCLC. Thus, miR-584 may serve as a tumor-suppressor, and the results of the present study provide a reference for future research into the potential mechanisms underlying NSCLC progression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]