Feline mammary carcinomas (FMCs) with anaplastic and malignant spindle cells histologically resemble the human metaplastic breast carcinoma (hMBC), spindle-cell subtype. hMBCs display epithelial-to-mesenchymal transition (EMT) characteristics. Herein we report the establishment and characterization of a cell line (TiHoCMglAdcar0906; TiHo-0906) exhibiting EMT-like properties derived from an FMC with anaplastic and malignant spindle cells. Copy-number variations (CNVs) by next-generation sequencing and immunohistochemical characteristics of the cell line and the tumour were compared. The absolute qPCR expression of EMT-related markers HMGA2 and CD44 was determined. The growth, migration, and sensitivity to doxorubicin were assessed. TiHo-0906 CNVs affect several genomic regions harbouring known EMT-, breast cancer-, and hMBCs-associated genes as AKT1, GATA3, CCND2, CDK4, ZEB1, KRAS, HMGA2, ESRP1, MTDH, YWHAZ, and MYC. Most of them were located in amplified regions of feline chromosomes (FCAs) B4 and F2. TiHo-0906 cells displayed an epithelial/mesenchymal phenotype, and high HMGA2 and CD44 expression. Growth and migration remained comparable during subculturing. Low-passaged cells were two-fold more resistant to doxorubicin than high-passaged cells (IC50: 99.97 nM, and 41.22 nM, respectively). The TiHo-0906 cell line was derived from a poorly differentiated cellular subpopulation of the tumour consistently displaying EMT traits. The cell line presents excellent opportunities for studying EMT on FMCs.

Chronic inflammation plays a central role in hepatocellular carcinoma (HCC), but the contribution of hepatocytes to tumor-associated inflammation is not clear. Here, we report that the zinc finger transcription factor Miz1 restricted hepatocyte-driven inflammation to suppress HCC, independently of its transcriptional activity. Miz1 was downregulated in HCC mouse models and a substantial fraction of HCC patients. Hepatocyte-specific Miz1 deletion in mice generated a distinct sub-group of hepatocytes that produced pro-inflammatory cytokines and chemokines, which skewed the polarization of the tumor-infiltrating macrophages toward pro-inflammatory phenotypes to promote HCC. Mechanistically, Miz1 sequestrated the oncoprotein metadherin (MTDH), preventing MTDH from promoting transcription factor nuclear factor κB (NF-κB) activation. A distinct sub-group of pro-inflammatory cytokine-producing hepatocytes was also seen in a subset of HCC patients. In addition, Miz1 expression inversely correated with disease recurrence and poor prognosis in HCC patients. Our findings identify Miz1 as a tumor suppressor that prevents hepatocytes from driving inflammation in HCC.

Keywords: HCC; MTDH; Miz1; hepatocellular carcinoma; hepatocyte NF-κB; inflammation; metadherin; scRNA-seq.

OBJECTIVE

To investigate the functional mechanism of metadherin (MTDH), hypoxia-inducible factor-1 alpha (HIF-1α) and transketolase-like gene 1 (TKTL1) and their interaction with each other in laryngeal carcinoma development.

METHODS

Thirty laryngeal carcinoma samples and 20 samples of para-carcinoma tissue were taken from the patients received operation treatment. The expression levels of MTDH, HIF-1α and TKTL1 were detected in all the samples by SP immunohistochemical methods. The data were analyzed by the SPSS13.0 statistical software.

RESULTS

The positive expression rate of MTDH, HIF-1α and TKTL1 in the 30 cases of laryngeal carcinoma was 56.67%, 60.00% and 63.33%, respectively, which was 20.00%,10.00% and 15.00% respectively in the para-carcinoma tissue, the difference of the positive expression rate of the tested objects between these two groups was statistically significant (P < 0.05 or P < 0.01). Of the 30 cases of laryngeal carcinoma, the positive expression rate of MTDH, HIF-1α and TKTL1 in the cases with lymphnode metastasis was 84.62%, 84.62% and 79.62%, respectively, compared with the rate in those without lymph nodes metastasis, which was 35.29%, 41.18% and 35.29%. The difference of the positive expression rate of the tested objects between these two groups was statistically significant (P < 0.05). In the tissue of poorly differentiated squamons cell carcinoma verified by pathology, the positive expression rates of MTDH and HIF-1α was 73.68% and 84.21%, respectively, while that in the tissue of well differentiated squamous carcinoma was 27.27% and 18.18%. The difference of the positive expression rate of the tested objects between these two groups was statistically significant (P < 0.05 or (P < 0.01). The positive expression rate of TKTL1 in laryngeal carcinoma at stage I-II was 25.00% and that at stage III-IV was 72.22%, the difference between which was statistically significant (P < 0.05). The positive expression rate of HIF-1α in laryngeal carcinoma at stage I-II was 33.33% and that at stage III-IV was 77. 78%, the difference between which was statistically significant (P < 0.05). The expression of MTDH, HIF-1α and TKTL1 showed no relationship with age,smoking amount or the tumor location (P>> 0.05). The Spearman's rank correlation analysis showed that the positive expression rates of MTDH and HIF-1α in laryngeal carcinoma had positive correlation (r = 0.384, P < 0.05); the positive expression rates of TKTL1 and HIF-1α in laryngeal carcinoma had positive correlation (r = 0.508, P < 0.01); But there was no significant correlation between the positive expression rates of MTDH and TKTL1 in laryngeal carcinoma (r = -0.107, P>> 0.05).

CONCLUSIONS

It suggested that these three proteins may have close relationship with the occurrence, invasion and metastasis of the laryngeal carcinoma. MTDH and TKTL1 may be expected to be new clinical targets for laryngeal carcinoma treatment and it could offer theoretical basis for the prognosis of the laryngeal carcinoma.

Numerous microRNAs (miRNAs) have been demonstrated to be downregulated or upregulated in hepatocellular carcinoma (HCC) and play important roles in its occurrence and development. Therefore, the investigation of miRNAs and their functions implicated in the genesis and development of HCC may provide key clues for the identification of effective therapeutic approaches for patients with this disease. The aims of the present study were to detect miRNA‑466 (miR‑466) expression in HCC tissues and cell lines and to determine its effects on HCC cell proliferation, apoptosis and metastasis, as well as to explore the mechanisms underlying the tumor‑suppressing roles of miR‑466 in HCC. In the present study, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was performed to detect miR‑466 expression in HCC tissues and cell lines. The effects of miR‑466 upregulation on HCC cell proliferation, apoptosis, migration and invasion were determined using Cell Counting Kit‑8 assay, flow cytometry analysis and Transwell chamber assay, respectively. The potential target gene of miR‑466 was predicted using bioinformatic analysis, which was further confirmed by luciferase reporter assay, RT‑qPCR and western blot analysis. It was found that miR‑466 was obviously decreased in HCC tissues and cell lines. The results of functional experiments revealed that restoration of miR‑466 expression suppressed the proliferation, induced apoptosis, and reduced the metastasis of HCC cells. In addition, metadherin (MTDH) was identified as a direct target of miR‑466 in HCC cells. Furthermore, MTDH was upregulated in HCC tissues, which was inversely correlated with the miR‑466 level. Moreover, inhibition of MTDH displayed similar tumor‑suppressing roles as miR‑466 upregulation in HCC cells. In addition, MTDH reintroduction restored the tumor‑suppressor activity of miR‑466 overexpression in HCC cells. These findings suggest that miR‑466 is a potential therapeutic tool for HCC therapy.

microRNA-1471 (miR-1471) is a newly identified miRNA that is downregulated in breast cancer. However, its biological roles in human tumors are largely unknown. This study aimed to investigate the clinical significance and functions of miR-1471 in glioma. We found miR-1471 expression was significantly reduced in glioma tissues and cell lines. Forced expression of miR-1471 remarkedly suppressed glioma cell proliferation and invasion. Notably, metadherin (MTDH) was validated as a direct target of miR-1471 and the restoration of MTDH expression reversed the inhibitory effects of miR-1471 on glioma cell proliferation and invasion. Also, low miR-1471 expression was a predictor for worse 5-year overall survival of glioma patients. Overall, these results reveal the tumor suppressive role of miR-1471 in glioma, highlighting the potential to consider miR-1471/MTDH axis as a therapeutic target for the treatment of glioma in the near future.

Prostate cancer is the second leading cause of cancer deaths among men in Western counties and has increased in incidence also in China in recent years. Although diagnosis modalities for primary prostate cancer have markedly improved, there are still no effective therapies for metastatic prostate cancer. SU6668 is an inhibitor of the tyrosine kinase activity of three angiogenic receptors VEGFR2, PDGFRβ and FGFR1. There is strong experimental evidence that SU6668 can induce growth inhibition of various primary tumors. However, the function and molecular mechanism of SU6668 in prostate cancer has not been fully elucidated. In the present study, we found that SU6668 inhibited the proliferation and invasion of prostate cancer cells. Functional studies also demonstrated that SU6668 inhibited epithelial-mesenchymal transition in DU145 and LNCap cells. After treatment with SU6668, MTDH protein, which has been reported to be significantly overexpressed in many human tumor tissues, was downregulated in DU145 and LNCap cells. siRNA-mediated silencing of MTDH in prostate cancer cells decreased their proliferation and invasive capabilities, suggesting that SU6668 may inhibit cell proliferation and invasion of prostate cancer cells partly through downstream targeting of MTDH. Mechanistic investigations showed that AKT signaling pathway was inhibited after SU6668 treatment in prostate cancer cells. Moreover, a combination of SU6668 and PI3K-AKT pathway inhibitor LY29004 resulted in increased inhibition of cell proliferation and invasion in DU145 cells. Taken together, our findings revealed that SU6668 suppressed prostate cancer progression by downregulating MTDH/AKT signaling pathway and identified a promising therapeutic strategy for prostate cancer.

Cancer development results from the acquisition of numerous genetic and epigenetic alterations in cancer cells themselves, as well as continuous changes in their microenvironment. The plasticity of cancer cells allows them to continuously adapt to selective pressures brought forth by exogenous environmental stresses, the internal milieu of the tumor and cancer treatment itself. Resistance to treatment, either inherent or acquired after the commencement of treatment, is a major obstacle an oncologist confronts in an endeavor to efficiently manage the disease. Resistance to chemotherapy, chemoresistance, is an important hallmark of aggressive cancers, and driver oncogene-induced signaling pathways and molecular abnormalities create the platform for chemoresistance. The oncogene Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) is overexpressed in a diverse array of cancers, and its overexpression promotes all the hallmarks of cancer, such as proliferation, invasion, metastasis, angiogenesis and chemoresistance. The present review provides a comprehensive description of the molecular mechanism by which AEG-1 promotes tumorigenesis, with a special emphasis on its ability to regulate chemoresistance.

Keywords: AEG-1; RNA binding; chemoresistance; protein–protein interaction; translational regulation.

AEG-1, also called MTDH, has oncogenic potential in numerous cancers and is considered a multifunctional modulator because of its involvement in developmental processes and inflammatory and degenerative brain diseases. However, the role of AEG-1 in astrocytes remains unknown. This study aimed to investigate proteins directly regulated by AEG-1 by analyzing their RNA expression patterns in astrocytes transfected with scramble shRNA and AEG-1 shRNA. AEG-1 knockdown down-regulated TWIK-1 mRNA. Real-time quantitative PCR (qPCR) and immunocytochemistry assays confirmed that AEG-1 modulates TWIK-1 mRNA and protein expression. Electrophysiological experiments further revealed that AEG-1 further regulates TWIK-1-mediated potassium currents in normal astrocytes. An RNA immunoprecipitation assay to determine how AEG-1 regulates the expression of TWIK-1 revealed that AEG-1 binds directly to TWIK-1 mRNA. Furthermore, TWIK-1 mRNA stability was significantly increased upon overexpression of AEG-1 in cultured astrocytes (p < 0.01). Our findings show that AEG-1 serves as an RNA-binding protein to regulate TWIK-1 expression in normal astrocytes.

Keywords: AEG-1; RNA-binding protein; TWIK-1; astrocyte.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

OBJECTIVE

To study the expression and predictive value of MTDH, Bcl-2 and E-cadherin in sinonasal malignant mucosal melanoma (SNM).

METHODS

Seventy-four formalin-fixed paraffin-embedded SNM specimens were subjected to immunohistochemical staining of MTDH, Bcl-2 and E-cadherin. Correlation between staining results and disease outcome was analyzed.SPSS 19.0 software was used to analyze the data.

RESULTS

Positive staining of MTDH, Bcl-2 and E-cadherin was observed in 56/74 (75.7%), 18/74 (24.3%) and 21/74 (28.4%) cases, respectively. MTDH positive patients had higher metastatic rate than MTDH negative patients (67.9% vs. 33.3%, P=0.009, OR=2.037, 95% CI: 1.034-4.016). Negative Bcl-2 was correlated with worse overall survival time (HR=2.023, P=0.025). Expression of E-cadherin was adversely associated with expression of MTDH (r=-0.315, P=0.006).

CONCLUSIONS

High MTDH expression and low Bcl-2 expression suggest poor prognosis of SNM, while the predictive value of E-cadherin needs further study.

[This retracts the article DOI: 10.2147/CMAR.S176887.].

Background & aims: Identifying novel and actional targets in hepatocellular carcinoma (HCC) remains an unmet medical need. TAK1 was originally identified as a TGF-β-activated kinase and was further proved to phosphorylate and activate numerous downstream targets and promote cancer progression. However, the role of TAK1 in developed HCC progression and targeted therapy resistance is poorly understood.

Methods: The expression of TAK1 or MTDH in HCC cell lines, tumor tissues, and sorafenib-resistant models was analyzed by in silico analysis, quantitative real-time PCR, western blotting and immunohistochemistry. In vivo and In vitro experiments was introduced to examine the function of TAK1 or MTDH in HCC and sorafenib resistance using small interfering RNA and pharmacological inhibitors in combination with or without sorafenib. Co-immunoprecipitation and RNA immunoprecipitation was carried out to determine the binding between TAK1 and FBXW2 or between MTDH and FBXW2 RNA. Protein half-life and in vitro ubiquitination experiment was performed to validate whether FBXW2 regulates TAK1 degradation.

Results: Our findings unraveled the clinical significance of TAK1 in promoting HCC and sorafenib resistance. We identified a novel E3 ubiquitin ligase, FBXW2, targeting TAK1 for K48-linked polyubiquitylation and subsequent degradation. We also found that MTDH contributes to TAK1 upregulation in HCC and sorafenib resistance, through binding to FBXW2 mRNA and accelerate its degradation. Moreover, combination of TAK1 inhibitor and sorafenib suppressed the growth of sorafenib-resistant HCCLM3 xenograft in mouse models.

Conclusions: These results revealed novel mechanism underlying TAK1 protein degradation and highlighted the therapeutic value of targeting TAK1 in suppressing HCC and overcoming sorafenib resistance.

Keywords: Drug resistance; Hepatocellular Carcinoma; Sorafenib; TAK1; Ubiquitin-mediated proteolysis.

Background: CircRNA plays an important role in cancer progression. However, the potential mechanism of circRNA in gastric cancer remains unknown. In this study, we aimed to investigate the specific mechanism of circALPL in gastric cancer. Methods: Using a high-throughput microarray, we found that circALPL was upregulated in gastric cancer cell lines. RT-qPCR was used to measure the circALPL expression level in gastric cell lines and tissue. Transwell, CCK-8, and metastasis assays were performed to learn the function after circALPL was inhibited. Results: circALPL downregulation suppresses the invasion and proliferation ability of gastric cancer cells. Additionally, the underlying pathway of circALPL was studied using luciferase reporter assays and RNA immunoprecipitation assays. The results showed that circALPL promotes gastric cancer progression by sponging miR-127, thus upregulating MTDH. Conclusion: The circALPL-miR-127-MTDH pathway plays a vital role in gastric cancer proliferation and metastasis. circALPL might be a new therapeutic target in gastric cancer.

Keywords: MTDH; circALPL; competitive endogenous RNAs; gastric cancer; microRNA.

Keywords: MTDH; PI3K/AKT; oral squamous cell carcinoma.

Taking advantage of reliable metabolic labeling and accurate isobaric MS2 quantification, we developed a global in vivo terminal amino acid labeling (G-IVTAL) strategy by combining metabolic labeling and isotopic dimethyl labeling for quantifying tryptic peptides. With G-IVTAL, the scale of qualitative and quantitative data can be increased twofold compared with in vivo termini amino acid labeling (IVTAL) in which Lys-N and Arg-C are used for digestion. As a result, up to 81.78% of the identified proteins have been confidently quantified in G-IVTAL-labeled HepG2 cells. Dialyzed serum has been used in most SILAC studies to ensure complete labeling. However, dialysis requires the removal of low molecular weight hormones, cytokines, and cellular growth factors, which are essential for the cell growth of certain cell lines. To address the influence of dialyzed serum in HepG2 growth, the G-IVTAL strategy was applied to quantify the expression differences between dialyzed serum- and normal serum-cultured HepG2 cells. Finally, we discovered 111 differentially expressed proteins, which could be used as references to improve the reliability of the SILAC quantification. Among these, by using western blotting, the differential expressions of MTDH, BCAP31, and GPC3 were confirmed as being influenced by dialyzed serum. The experimental results demonstrate that the G-IVTAL strategy is a powerful tool to achieve accurate and reliable protein quantification.

Background: Breast cancer, the most common cancer in women worldwide, causes the vast majority of cancer-related deaths. Undoubtedly, tumor metastasis and recurrence are responsible for more than 90 percent of these deaths. MicroRNAs are endogenous noncoding RNAs that have been integrated into almost all the physiological and pathological processes, including metastasis. In the present study, the role of miR-128 in breast cancer was investigated.

Results: Compared to the corresponding adjacent normal tissue, the expression of miR-128 was significantly suppressed in human breast cancer specimens. More importantly, its expression level was reversely correlated to histological grade of the cancer. Ectopic expression of miR-128 in the aggressive breast cancer cell line MDA-MB-231 could inhibit cell motility and invasive capacity remarkably. Afterwards, Metadherin (MTDH), also known as AEG-1 (Astrocyte Elevated Gene 1) and Lyric that implicated in various aspects of cancer progression and metastasis, was further identified as a direct target gene of miR-128 and its expression level was up-regulated in clinical samples as expected. Moreover, knockdown of MTDH in MDA-MB-231 cells obviously impaired the migration and invasion capabilities, whereas re-expression of MTDH abrogated the suppressive effect caused by miR-128.

Conclusions: Overall, these findings demonstrate that miR-128 could serve as a novel biomarker for breast cancer metastasis and a potent target for treatment in the future.

Keywords: Breast cancer; MTDH; Metastasis; miR-128.

Recently, the term healthy lifestyle connected to low-calorie diets, although it is not possible to get rid of added sugars as a source of energy, despite the close relation of added sugars to some diseases such as obesity, diabetes, etc. As a result, the sweetener market has flourished, which has led to increased demand for natural sweeteners such as polyols, including d-mannitol. Various methods have been developed to produce d-mannitol to achieve high productivity and low cost. In particular, metabolic engineering for d-mannitol considers one of the most promising approaches for d-mannitol production on the industrial scale. To date, the chemical process is not ideal for large-scale production because of its multistep mechanism involving hydrogenation and high cost. In this review, we highlight and present a comparative evaluation of the biochemical parameters that affecting d-mannitol synthesis from Thermotoga neapolitana and Thermotoga maritima mannitol dehydrogenase (MtDH) as a potential contribution for d-mannitol bio-synthesis. These species were selected because purified mannitol dehydrogenases from both strains have been reported to produce d-mannitol with no sorbitol formation under temperatures (90-120 °C).

Keywords: Highly thermostable; Hyperthermophilic archaea; Mannitol dehydrogenases; MtDH; d-fructose; d-mannitol.

Overexpression of metadherin/astrocyte elevated gene-1 (MTDH/AEG-1) has been implicated in various cancers. However, the clinical significance and the potential biological functions of MTDH/AEG-1 in bladder urothelial carcinoma (BUC) are not established.

In this study, the expression of MTDH/AEG-1in BUC was measured using the Cancer Genome Atlas (TCGA) database and immunohistochemistry, together with a meta-analysis, to investigate the expression and diagnostic value of MTDH/AEG-1. The possible association between MTDH/AEG-1 expression and the viability, proliferation, and apoptosis in BUC cell lines (T24, HT1376, and RT4) was also assessed in vitro by viability, MTS, colony formation, and caspase-3/7 assays, as well as Hoechst 33342 and propidium iodide (PI) double staining.MTDH/AEG-1 expression was significantly higher in BUC tissues than in normal bladder tissues, according to the TCGA and immunohistochemistry results, and these findings were verified by the meta-analysis. Functional knockdown of MTDH/AEG-1 suppressed BUC cell growth and induced apoptosis. Bioinformatics analyses indicated an involvement of MTDH/AEG-1 in several processes, including RNA binding, protein transport, intracellular transport, and the insulin signaling pathway.We hypothesize that MTDH/AEG-1 could play essential roles in BUC, especially in cell growth and apoptosis, via the insulin signaling pathway."

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.

Glioma is a well‑known aggressive and malignant brain tumor, and accounts for ~30% of all brain and central nervous system tumors. A number of studies have indicated that the abnormal expression of specific microRNAs (miR) serves vital roles in the tumorigenesis and tumor development of human cancer, including glioma. miR‑216b has been studied in a number of types of cancer. However, the expression pattern, molecular function and underlying mechanisms of miR‑216b in glioma remain unclear. In the present study, it was demonstrated that the level of miR‑216b was significantly decreased in glioma tissues and cell lines compared with matched normal tissues and primary normal human astrocytes. The reduced miR‑216b expression level was correlated with the Karnofsky Performance Score and the World Health Organization grade of gliomas. Upregulation of miR‑216b repressed cell proliferation and invasion in glioma. Additionally, metadherin (MTDH) was identified as a direct target gene of miR‑216b in glioma. MTDH expression was demonstrated to be significantly upregulated and inversely associated with miR‑216b expression in glioma specimens. MTDH knockdowns could simulate the cellular conditions induced by miR‑216b overexpression in glioma cells. In addition, miR‑216b regulated phosphatidylinositol 3,4,5‑trisphosphate 3‑phosphatase and dual‑specificity protein phosphatase PTEN/protein kinase B signaling pathways in glioma. These results suggested that miR‑216b acted as a tumor suppressor in glioma by directly targeting MTDH and that the miR‑216b/MTDH axis may be an effective therapeutic target for the treatment of patients with this disease.

Therapies against malignant pleural mesothelioma (MPM) have yielded disappointing results, in part, because pathologic mechanisms remain obscure. In searching for rational molecular targets, we identified metadherin (MTDH), a multifunctional gene associated with several tumor types but previously unrecognized in MPM. Cox proportional hazards regression analysis delineated associations between higher MTDH expression and lower patient survival from three independent MPM cohorts (n = 349 patients). Through in vitro assays with overexpression and downregulation constructs in MPM cells, we characterized the role of MTDH. We confirmed in vivo the phenotype of altered MTDH expression in a murine xenograft model. Transcriptional regulators of MTDH were identified by chromatin immunoprecipitation. Overexpression of both MTDH mRNA (12-fold increased) and protein levels was observed in tumor tissues. MTDH stable overexpression significantly augmented proliferation, invasiveness, colony formation, chemoresistance, and an antiapoptosis phenotype, while its suppression showed opposite effects in MPM cells. Interestingly, NF-κB and c-Myc (in a feed-forward loop motif) contributed to modulating MTDH expression. Knockdown of MTDH expression profoundly retarded xenograft tumor growth. Thus, our findings support the notion that MTDH integrates upstream signals from certain transcription factors and mediates pathogenic interactions contributing to MPM traits. MTDH represents a new MPM-associated gene that can contribute to insights of MPM biology and, as such, suggest other treatment strategies.