Formin-like 1 (FMNL1) Is Associated with Glioblastoma Multiforme Mesenchymal Subtype and Independently Predicts Poor Prognosis

Glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults, is characterized by rapid proliferation, aggressive migration, and invasion into normal brain tissue. Formin proteins have been implicated in these processes. However, the role of formin-like 1 (FMNL1) in cancer remains unclear. We studied FMNL1 expression in glioblastoma samples using immunohistochemistry. We sought to analyze the correlation between FMNL1 expression, clinicopathologic variables, and patient survival. Migration and invasion assays were used to verify the effect of FMNL1 on glioblastoma cell lines. Microarray data were downloaded from The Cancer Genome Atlas and analyzed using gene set enrichment analysis (GSEA). FMNL1 was an independent predictor of poor prognosis in a cohort of 217 glioblastoma multiforme cases (p < 0.001). FMNL1 expression was significantly higher in the mesenchymal subtype. FMNL1 upregulation and downregulation were associated with mesenchymal and proneural markers in the GSEA, respectively. These data highlight the important role of FMNL1 in the neural-to-mesenchymal transition. Conversely, FMNL1 downregulation suppressed glioblastoma multiforme cell migration and invasion via DIAPH1 and GOLGA2, respectively. FMNL1 downregulation also suppressed actin fiber assembly, induced morphological changes, and diminished filamentous actin. FMNL1 is a promising therapeutic target and a useful biomarker for GBM progression.

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ANGI-06. FUNCTION OF FORMIN-LIKE 1 (FMNL1) IN GLIOBLASTOMA MULTIFORME

Neuro-Oncology ◽

10.1093/neuonc/noz175.117 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi31-vi31

Author(s):

Nayuta Higa ◽

Yoshinari Shinsato ◽

Tomoko Takajyo ◽

Hajime Yonezawa ◽

Hiroyuki Uchida ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Cancer Progression ◽

Morphological Changes ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

University Hospital ◽

Migration And Invasion ◽

Normal Brain ◽

Filamentous Actin ◽

Invasion And Migration

Abstract INTRODUCTION Glioblastoma multiforme is the most common primary malignant brain tumour in adults. It is characterised by rapid proliferation, aggressive migration, and invasion into normal brain tissue. Formin proteins have been implicated in cancer progression, invasion, and migration. However, the role of FMNL1 in cancer remains unclear. We are the first to investigate FMNL1 in GBM. METHODS Clinical specimens were obtained from tumours surgically removed and pathologically confirmed as GBM from 217 GBM patients treated from 2000 to 2015 at the Department of Neurosurgery, Kagoshima University Hospital. We studied the expression of FMNL1 in glioblastoma samples by immunohistochemistry to analyse the correlation between FMNL1 expression, clinicopathologic variables, and patient survival. Migration and invasion assays were used to verify the effect of FMNL1 on glioblastoma cell lines. Microarray data were downloaded from TCGA and analysed using Gene Set Enrichment Analysis (GSEA). RESULTS FMNL1 was found to be a predictor of poor prognosis in a cohort of 217 cases (P < 0.001). GSEA showed that upregulation and downregulation of FMNL1 were associated with mesenchymal and proneural markers, respectively. Contrarily, downregulation of FMNL1 suppressed migration and invasion of glioblastoma multiforme cells via DIAPH1 and GOLGA2, respectively. Downregulation of FMNL1 also suppressed assembly of actin fibres, induced morphological changes, and diminished filamentous actin. CONCLUSION Our studies show that abundant FMNL1 expression in GBM patients is correlated with an unfavourable prognosis. FMNL1 is a promising therapeutic target and a useful biomarker for GBM progression.

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GPD1L Suppresses Colon Adenocarcinoma Via Repressing TGFβ1/EMT

10.21203/rs.3.rs-1120400/v1 ◽

2021 ◽

Author(s):

Yunqi Li ◽

Minghao Liu ◽

zhu xiang ◽

Xuhui Yang ◽

Hui Liu

Keyword(s):

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Colon Adenocarcinoma ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Human Beings ◽

Mesenchymal Transition ◽

Adenocarcinoma Cells ◽

Colon Adenocarcinoma Cells

Abstract Colon adenocarcinoma is one of the most prevalent malignant tumors in human beings. Hence, the identification of valuable biomarkers and therapeutic targets is vital for improved treatment and patient outcomes. The role of glycerol-3-phosphate dehydrogenase 1-like (GPD1L) in several tumors has been achieved in recent years. However, the underlying mechanisms of GPD1L in colon adenocarcinoma remain elusive. In this study, we identified that GPD1L was associated with better prognosis in colon adenocarcinoma patients using gene expression omnibus (GEO) and the cancer genome atlas (TCGA) database. In addition, knockdown of GPD1L promoted the proliferation, migration and invasion and reversed by re-expression GPD1L in colon adenocarcinoma cells in vitro. According to gene set enrichment analysis (GSEA), GPD1L is closely correlated with transforming growth factor-β (TGFβ) signaling pathway in colon adenocarcinoma. Moreover, GPD1L downregulates epithelial mesenchymal transition (EMT) marker proteins via TGFβ1 due to Western blot analysis. These findings demonstrate that GPD1L inhibits the growth of colon adenocarcinoma cells by inhibiting EMT induced by TGFβ1. GPD1L may be a promising molecular target for the treatment of colon adenocarcinoma patients.

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RETRACTED ARTICLE: Sorcin Predicts Poor Prognosis and Promotes Metastasis by Facilitating Epithelial-mesenchymal Transition in Hepatocellular Carcinoma

Scientific Reports ◽

10.1038/s41598-017-10365-3 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 4

Author(s):

Xiong Lei ◽

Yahang Liang ◽

Jian Chen ◽

Shuai Xiao ◽

Jian Lei ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Poor Prognosis ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Significant Risk ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Multiple Tumor ◽

Liver Tissues

Abstract Metastasis-associated recurrence is the main cause for the poor prognosis of hepatocellular carcinoma (HCC). However, the detailed molecular mechanisms underlying HCC metastasis remain elusive. Though some data indicated the oncogenic role of Sorcin in tumors, the prognostic value and biological role of Sorcin in HCC is still unknown. In this study, it demonstrated that Sorcin expression levels were significantly upregulated in HCC tumor tissues compared with matched adjacent nontumorous liver tissues and normal liver tissues, and such expression level correlated with HCC metastasis. High Sorcin expression was significantly correlated with aggressive clinicopathological characteristics such as multiple tumor nodules, high Edmondson-Steiner grade, microvascular invasion, advanced TNM stage and advanced BCLC stage (all P < 0.05). HCC patients with high Sorcin expression had both shorter survival and higher recurrence than those with low Sorcin expression (all P < 0.05). Sorcin expression was an independent and significant risk factor for survival and recurrence of HCC patients. Results of functional experiments showed that Sorcin could promote HCC cell proliferation, migration, and invasion in vitro, and facilitate HCC growth and metastasis in vivo. Mechanistically, Sorcin exerted its role by activating extracellular signal-regulated kinase (ERK) pathway and promoted metastasis by facilitating epithelial-mesenchymal transition (EMT) in HCC.

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Inhibition of MUC1 exerts cell-cycle arrest and telomerase suppression in glioblastoma cells

Scientific Reports ◽

10.1038/s41598-020-75457-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sojin Kim ◽

Youngbeom Seo ◽

Tamrin Chowdhury ◽

Hyeon Jong Yu ◽

Chae Eun Lee ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Transforming Growth Factor ◽

Gene Set Enrichment Analysis ◽

Telomere Maintenance ◽

Normal Brain ◽

Mesenchymal Transition ◽

Maintenance Mechanism ◽

Cycle Arrest

Abstract Mucin 1 (MUC1) is a transmembrane glycoprotein involved in tumorigenesis of diverse cancers. However, the role of MUC1 in glioblastoma (GBM) has not yet been fully explored. In this study, the anticancer mechanism of MUC1 suppression in GBM was investigated. The expression level of MUC1 was analyzed in human glioma and paired normal brain tissues. MUC1 was overexpressed in GBM and was negatively associated with overall survival. Moreover, we silenced MUC1 to investigate its effect in GBM cell lines and found that knockdown of MUC1 inhibited cell proliferation and resulted in cell cycle arrest at G1 phase. MUC1 silencing decreased the phosphorylation of RB1 and increased the expression of CDKN1B. Gene set enrichment analysis showed that a series of genes related to cell cycle, telomere maintenance and transforming growth factor Beta (TGF-β) signaling in epithelial mesenchymal transition (EMT) were influenced by MUC1 knockdown. Notably, the reduced TERT expression levels combined with impaired telomerase activity and the switching of telomere maintenance mechanism to alternative lengthening of telomeres (ALT) were observed after MUC1 knockdown. Our results support the role of MUC1 in oncological process in GBM which can be developed as a therapeutic target for cell cycle control and telomere maintenance mechanism.

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Expression of lactate dehydrogenase C correlates with poor prognosis in renal cell carcinoma

Tumor Biology ◽

10.1177/1010428317695968 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769596 ◽

Cited By ~ 8

Author(s):

Yibo Hua ◽

Chao Liang ◽

Jundong Zhu ◽

Chenkui Miao ◽

Yajie Yu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Lactate Dehydrogenase ◽

Cell Carcinoma ◽

Renal Cell ◽

Poor Prognosis ◽

Carcinoma Cells ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Lactate Dehydrogenase C

Lactate dehydrogenase C is an isoenzyme of lactate dehydrogenase and a member of the cancer–testis antigens family. In this study, we aimed to investigate the expression and functional role of lactate dehydrogenase C and its basic mechanisms in renal cell carcinoma. First, a total of 133 cases of renal cell carcinoma samples were analysed in a tissue microarray, and Kaplan–Meier survival curve analyses were performed to investigate the correlation between lactate dehydrogenase C expression and renal cell carcinoma progression. Lactate dehydrogenase C protein levels and messenger RNA levels were significantly upregulated in renal cell carcinoma tissues, and the patients with positive lactate dehydrogenase C expression had a shorter progression-free survival, indicating the oncogenic role of lactate dehydrogenase C in renal cell carcinoma. In addition, further cytological experiments demonstrated that lactate dehydrogenase C could prompt renal cell carcinoma cells to produce lactate, and increase metastatic and invasive potential of renal cell carcinoma cells. Furthermore, lactate dehydrogenase C could induce the epithelial–mesenchymal transition process and matrix metalloproteinase-9 expression. In summary, these findings showed lactate dehydrogenase C was associated with poor prognosis in renal cell carcinoma and played a pivotal role in the migration and invasion of renal cell carcinoma cells. Lactate dehydrogenase C may act as a novel biomarker for renal cell carcinoma progression and a potential therapeutic target for the treatment of renal cell carcinoma.

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COPB2: A Novel Prognostic Biomarker That Affects Progression of HCC

BioMed Research International ◽

10.1155/2021/6648078 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Jiayao Zhang ◽

Xiaoyu Wang ◽

Guangbing Li ◽

Jingyi He ◽

Ziwen Lu ◽

...

Keyword(s):

Survival Analysis ◽

Epithelial Mesenchymal Transition ◽

Prognostic Biomarker ◽

Cancer Genome ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Migration And Invasion ◽

Clinicopathologic Characteristics ◽

Mesenchymal Transition ◽

Kaplan Meier

Purpose. This study is aimed at investigating the expression, underlying biological function, and clinical significance of coatomer protein complex subunit beta 2 (COPB2) in hepatocellular carcinoma (HCC). Methods. HCC-related data were extracted from The Cancer Genome Atlas (TCGA) database, International Cancer Genome Consortium (ICGC) database, and Gene Expression Omnibus (GEO) database. A logistic regression module was applied to analyze the relationship between the expression of COPB2 and clinicopathologic characteristics. The Cox proportional hazard regression model and Kaplan–Meier method were used for survival analysis. Gene set enrichment analysis (GSEA) was used to annotate the underlying biological functions. Loss-of-function experiments were conducted to determine the underlying mechanisms. Results. COPB2 was overexpressed in HCC, and high expression of COPB2 was significantly correlated with higher alpha fetoprotein (AFP) (odds ratio OR = 1.616 , >20 vs. ≤20, p < 0.05 ), stage ( OR = 1.744 , III vs. I, p < 0.05 ), and grade ( OR = 1.746 , G4+G3 vs. G2+G1, p < 0.05 ). Kaplan–Meier survival analysis showed that HCC patients with high COPB2 expression had a worse prognosis than those with low COPB2 expression ( p < 0.0001 for TCGA cohort, p < 0.05 for ICGC cohort). The univariate Cox (hazard ratio HR = 1.068 , p < 0.0001 ) and multivariate Cox ( HR = 2.011 , p < 0.05 ) regression analyses suggested that COPB2 was an independent risk factor. GSEA showed that mTOR and other tumor-related signaling pathways were differentially enriched in the high COPB2 expression phenotype. Silencing of COPB2 inhibited the proliferation, migration, and invasion abilities by suppressing epithelial-mesenchymal transition and mTOR signaling. Conclusion. COPB2 is a novel prognostic biomarker and a promising therapeutic target for HCC.

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NKCC1 involvement in the epithelial-to-mesenchymal transition is a prognostic biomarker in gliomas

PeerJ ◽

10.7717/peerj.8787 ◽

2020 ◽

Vol 8 ◽

pp. e8787

Author(s):

Huaiyu Sun ◽

Shengrong Long ◽

Bingbing Wu ◽

Jia Liu ◽

Guangyu Li

Keyword(s):

Epithelial Mesenchymal Transition ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

High Expression ◽

Migration And Invasion ◽

Intracranial Tumors ◽

Transwell Assay ◽

Western Blots ◽

Mesenchymal Transition ◽

Expression Levels

Background Gliomas are the most prevalent type of intracranial tumors. NKCC1 is an important regulator in tumor cell volume. We noticed that abnormally high NKCC1 expression resulted in changes in the shape and adhesion of glioma cells. However, little is known about the role of NKCC1 in the epithelial-mesenchymal transition (EMT) of gliomas. This study aims to clarify the biological function of NKCC1 in glioblastoma multiforme (GBM) progression. Methods Using data from The Cancer Genome Atlas (TCGA), we performed a Kaplan–Meier analysis on NKCC1 expression levels to estimate the rate of survival of mesenchymal GBM patients. The correlation between NKCC1 and EMT-related proteins was analyzed from the Gene Expression Profiling Interactive Analysis (GEPIA) server. We conducted Gene Set Enrichment Analysis (GSEA) to verify molecular signatures and pathways. We then studied the expression of NKCC1 in grade I–IV glioma tissue samples collected from patients using immunohistochemistry (IHC). Finally, we evaluated the effects of NKCC1 migration and invasion on the cellular behaviors of U251 cells using the transwell assay and western blots. Results High NKCC1 expression was associated with poor prognoses in mesenchymal GBM. Our results suggest a correlation between NKCC1 and EMT-protein markers: CDH2 and VIM. GSEA showed that gliomas, TGF-beta signaling and EMT were enriched in the NKCC1 high expression phenotype. Higher expression levels of NKCC1 in gliomas correlate with higher glioma grades. Transwell assay and western blot results demonstrated that the knockdown of NKCC1 led to a reduction in migration and invasion, while also inhibiting MMP-2 and MMP-9 expression in U251. Conclusion These results suggest that high expression of NKCC1 regulates EMT in gliomas, providing a new therapeutic strategy for addressing the spread of gliomas by inhibiting the spread of intracranial tumors.

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Genomic stratification based on microenvironment immune types and PD-L1 for tailoring therapeutic strategies in bladder cancer

BMC Cancer ◽

10.1186/s12885-021-08350-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xintong Lyu ◽

Ping Wang ◽

Qiao Qiao ◽

Yuanjun Jiang

Keyword(s):

Overall Survival ◽

Bladder Cancer ◽

Critical Role ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Prognostic Role ◽

Mesenchymal Transition ◽

Expression Levels ◽

Significant Difference

Abstract Background The tumour microenvironment (TME) not only plays a role during tumour progression and metastasis but also profoundly influences treatment efficacy. Environment-mediated drug resistance is a result of crosstalk between tumour cells and stroma. The presence of a “stromal exhaustion” response is suggested by the T cell exhaustion signature and PD-L1 expression. The prognostic role of PD-L1 in bladder cancer has been investigated in previous studies, but the results remain inconclusive. For a more comprehensive study, we discuss potential strategies to improve effectiveness in patients with various TME statuses and PD-L1 expression levels. Methods We estimated the prognostic role of PD-L1 using immunohistochemistry and identified four immune subtypes according to the type of stromal immune modulation and PD-L1 expression status. Results Patients in the PD-L1-low-exhausted group had the worst prognosis and showed the worst antigen-presenting cell (APC) immunosuppression status. The PD-L1-low-exhausted group showed the highest amount of infiltration by macrophage M2 cells, naïve B cells and resting mast cells. The TMB and the effectiveness of anti-PD-1 treatment were significantly increased in the PD-L1-high expression groups compared with the PD-L1-low expression groups. In the PD-L1-high groups, patients who underwent chemotherapy exhibited better overall survival rates than patients who did not undergo chemotherapy, whereas there was no significant difference in the PD-L1-low groups. We performed gene set enrichment analysis (GSEA) to explore the critical pathways that were active in the PD-L1-low-exhausted group, including the myogenesis, epithelial-mesenchymal transition and adipogenesis pathways. Copy number variations (CNVs) were related to the expression levels of differentially expressed genes upregulated in the PD-L1-low-exhausted group, including LCNL1, FBP1 and RASL11B. In addition, RASL11B played a role in predicting overall survival according to The Cancer Genome Atlas data, and this finding was validated in the PD-L1-low-exhausted group in the Gene Expression Omnibus database (GEO). Conclusion The immune environment of tumours plays an important role in the therapeutic response rate, and defining the immune groups plays a critical role in predicting disease outcome and strategy effectiveness.

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TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01690-z ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Qiang Tang ◽

Jinhuang Chen ◽

Ziyang Di ◽

Wenzheng Yuan ◽

Zili Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Poor Prognosis ◽

Transforming Growth Factor ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Dependent Manner ◽

Cancer Stemness ◽

Mesenchymal Transition ◽

Sphere Formation

Abstract Background Transmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. However, the role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive. Methods We investigated the expression of TM4SF1 in the Oncomine, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of CRC tissues. The effect of TM4SF1 on the epithelial-to-mesenchymal transition (EMT) and cancer stemness of CRC cells was investigated by Transwell, wound healing and sphere formation assays. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which TM4SF1 modulates EMT and cancer stemness in CRC. Results TM4SF1 expression was markedly higher in CRC tissues than in non-tumour tissues and was positively correlated with poor prognosis. Downregulation of TM4SF1 inhibited the migration, invasion and tumour sphere formation of SW480 and LoVo cells. Conversely, TM4SF1 overexpression significantly enhanced the migration, invasion and tumoursphere formation potential of CRC cells, Additionally, TM4SF1 silencing inhibited the EMT mediated by transforming growth factor-β1 (TGF-β1). Mechanistically, gene set enrichment analysis (GSEA) predicted that the Wnt signalling pathway was one of the most impaired pathways in TM4SF1-deficient CRC cells compared to controls. The results were further validated by WB, which revealed that TM4SF1 modulated SOX2 expression in a Wnt/β-catenin activation-dependent manner. Furthermore, we found that knockdown of TM4SF1 suppressed the expression of c-Myc, leading to decreased c-Myc binding to the SOX2 gene promoter. Finally, depletion of TM4SF1 inhibited metastasis and tumour growth in a xenograft mouse model. Conclusion Our study substantiates a novel mechanism by which TM4SF1 maintains cancer cell stemness and EMT via the Wnt/β-catenin/c-Myc/SOX2 axis during the recurrence and metastasis of CRC.

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Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Cancers ◽

10.3390/cancers12010098 ◽

2019 ◽

Vol 12 (1) ◽

pp. 98 ◽

Cited By ~ 3

Author(s):

Hsun-Hua Lee ◽

Che-Hsuan Lin ◽

Hui-Yu Lin ◽

Chia-Hao Kuei ◽

Jing-Quan Zheng ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Family Member ◽

Cell Lines ◽

Interaction Network ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Mesenchymal Transition ◽

Tnf Α ◽

High Level

Glioblastoma multiforme (GBM) is the most aggressive brain tumor and has a poor prognosis and is poorly sensitive to radiotherapy or temozolomide (TMZ) chemotherapy. Therefore, identifying new biomarkers to predict therapeutic responses of GBM is urgently needed. By using The Cancer Genome Atlas (TCGA) database, we found that the upregulation of histone 2A family member J (H2AFJ), but not other H2AFs, is extensively detected in the therapeutic-insensitive mesenchymal, IDH wildtype, MGMT unmethylated, or non-G-CIMP GBM and is associated with poor TMZ responsiveness independent of radiation. Similar views were also found in GBM cell lines. Whereas H2AFJ knockdown diminished TMZ resistance, H2AFJ overexpression promoted TMZ resistance in a panel of GBM cell lines. Gene set enrichment analysis (GSEA) revealed that H2AFJ upregulation accompanied by the activation of TNF-α/NF-κB and IL-6/STAT3-related pathways is highly predicted. Luciferase-based promoter activity assay further validated that the activities of NF-κB and STAT3 are causally affected by H2AFJ expression in GBM cells. Moreover, we found that therapeutic targeting HADC3 by tacedinaline or NF-κB by ML029 is likely able to overcome the TMZ resistance in GBM cells with H2AFJ upregulation. Significantly, the GBM cohorts harboring a high-level H2AFJ transcript combined with high-level expression of TNF-α/NF-κB geneset, IL-6/STAT3 geneset or HADC3 were associated with a shorter time to tumor repopulation after initial treatment with TMZ. These findings not only provide H2AFJ as a biomarker to predict TMZ therapeutic effectiveness but also suggest a new strategy to combat TMZ-insensitive GBM by targeting the interaction network constructed by TNF-α/NF-κB, IL-6/STAT3, HDAC3, and H2AFJ.

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