BMP signaling is a therapeutic target in ovarian cancer

AbstractHistone deacetylases (HDACs) are involved in tumor progression, and some have been successfully targeted for cancer therapy. The expression of histone deacetylase 4 (HDAC4), a class IIa HDAC, was upregulated in our previous microarray screen. However, the role of HDAC4 dysregulation and mechanisms underlying tumor growth and metastasis in nasopharyngeal carcinoma (NPC) remain elusive. Here, we first confirmed that the HDAC4 levels in primary and metastatic NPC tissues were significantly increased compared with those in normal nasopharyngeal epithelial tissues and found that high HDAC4 expression predicted a poor overall survival (OS) and progression-free survival (PFS). Functionally, HDAC4 accelerated cell cycle G1/S transition and induced the epithelial-to-mesenchymal transition to promote NPC cell proliferation, migration, and invasion in vitro, as well as tumor growth and lung metastasis in vivo. Intriguingly, knockdown of N-CoR abolished the effects of HDAC4 on the invasion and migration abilities of NPC cells. Mechanistically, HDAC3/4 binds to the E-cadherin promoter to repress E-cadherin transcription. We also showed that the HDAC4 inhibitor tasquinimod suppresses tumor growth in NPC. Thus, HDAC4 may be a potential diagnostic marker and therapeutic target in patients with NPC.

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Overexpressed P75CUX1 promotes EMT in glioma infiltration by activating β-catenin

Cell Death and Disease ◽

10.1038/s41419-021-03424-1 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Anqi Xu ◽

Xizhao Wang ◽

Jie Luo ◽

Mingfeng Zhou ◽

Renhui Yi ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Tumor Grade ◽

Prognostic Indicator ◽

Migration And Invasion ◽

Poor Overall Survival ◽

Mesenchymal Transition ◽

Kaplan Meier ◽

Homeobox Protein

AbstractThe homeobox protein cut-like 1 (CUX1) comprises three isoforms and has been shown to be involved in the development of various types of malignancies. However, the expression and role of the CUX1 isoforms in glioma remain unclear. Herein, we first identified that P75CUX1 isoform exhibited consistent expression among three isoforms in glioma with specifically designed antibodies to identify all CUX1 isoforms. Moreover, a significantly higher expression of P75CUX1 was found in glioma compared with non-tumor brain (NB) tissues, analyzed with western blot and immunohistochemistry, and the expression level of P75CUX1 was positively associated with tumor grade. In addition, Kaplan–Meier survival analysis indicated that P75CUX1 could serve as an independent prognostic indicator to identify glioma patients with poor overall survival. Furthermore, CUX1 knockdown suppressed migration and invasion of glioma cells both in vitro and in vivo. Mechanistically, this study found that P75CUX1 regulated epithelial–mesenchymal transition (EMT) process mediated via β-catenin, and CUX1/β-catenin/EMT is a novel signaling cascade mediating the infiltration of glioma. Besides, CUX1 was verified to promote the progression of glioma via multiple other signaling pathways, such as Hippo and PI3K/AKT. In conclusion, we suggested that P75CUX1 could serve as a potential prognostic indicator as well as a novel treatment target in malignant glioma.

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PRMT1 enhances oncogenic arginine methylation of NONO in colorectal cancer

Oncogene ◽

10.1038/s41388-020-01617-0 ◽

2021 ◽

Author(s):

Xin-Ke Yin ◽

Yun-Long Wang ◽

Fei Wang ◽

Wei-Xing Feng ◽

Shao-Mei Bai ◽

...

Keyword(s):

Colorectal Cancer ◽

Locally Advanced ◽

Xenograft Model ◽

Arginine Methylation ◽

Mass Spectrometry Analysis ◽

Migration And Invasion ◽

Poor Overall Survival ◽

Potential Marker

AbstractArginine methylation is an important posttranslational modification catalyzed by protein arginine methyltransferases (PRMTs). However, the role of PRMTs in colorectal cancer (CRC) progression is not well understood. Here we report that non-POU domain-containing octamer-binding protein (NONO) is overexpressed in CRC tissue and is a potential marker for poor prognosis in CRC patients. NONO silencing resulted in decreased proliferation, migration, and invasion of CRC cells, whereas overexpression had the opposite effect. In a xenograft model, tumors derived from NONO-deficient CRC cells were smaller than those derived from wild-type (WT) cells, and PRMT1 inhibition blocked CRC xenograft progression. A mass spectrometry analysis indicated that NONO is a substrate of PRMT1. R251 of NONO was asymmetrically dimethylated by PRMT1 in vitro and in vivo. Compared to NONO WT cells, NONO R251K mutant-expressing CRC cells showed reduced proliferation, migration, and invasion, and PRMT1 knockdown or pharmacological inhibition abrogated the malignant phenotype associated with NONO asymmetric dimethylation in both KRAS WT and mutant CRC cells. Compared to adjacent normal tissue, PRMT1 was highly expressed in the CRC zone in clinical specimens, which was correlated with poor overall survival in patients with locally advanced CRC. These results demonstrate that PRMT1-mediated methylation of NONO at R251 promotes CRC growth and metastasis, and suggest that PRMT1 inhibition may be an effective therapeutic strategy for CRC treatment regardless of KRAS mutation status.

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Snail Driving Alternative Splicing of CD44 by ESRP1 Enhances Invasion and Migration in Epithelial Ovarian Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000484458 ◽

2017 ◽

Vol 43 (6) ◽

pp. 2489-2504 ◽

Cited By ~ 16

Author(s):

Le Chen ◽

Ying Yao ◽

Lijuan Sun ◽

Jiajia Zhou ◽

Minmin Miao ◽

...

Keyword(s):

Ovarian Cancer ◽

Alternative Splicing ◽

Epithelial Ovarian Cancer ◽

Epithelial Mesenchymal Transition ◽

Regulatory Protein ◽

Cell Counting ◽

Migration And Invasion ◽

Mesenchymal Transition

Background/Aims: Our study aims to investigate the role, effect and mechanisms of ESRP1 (epithelial splicing regulatory protein 1) in epithelial-mesenchymal transition (EMT) in epithelial ovarian cancer (EOC). Methods: Microarray and immunohistochemical analysis of ESRP1 expression were performed in EOC cases. The correlations between ESRP1 expression and clinical factors on EOC were assessed. Lentivirus-mediated RNA interference and EGFP vector which contains ESRP1 gene were used to down-regulate and up-regulate ESRP1 expression in human EOC cell lines. Roles of ESRP1 in cell growth, migration and invasion of EOC cells were also measured by Cell Counting Kit-8 and Transwell systems in vitro and by a nude mice intraperitoneal transplantation model in vivo. Results: By the analysis of Gene Expression Omnibus (GEO) (p<0.05) and our own microarray data (p<0.001), ESRP1 expression in EOC was significantly different from normal ovarian tissue. It was abundant in the nuclei of cancer cells and in malignant lesions. However, it was weakly expressed or negative in both normal and benign lesions. High ESRP1 expression in EOC was associated with poor clinical outcomes. Decreased ESRP1 expression significantly increased cell migration and invasion both in vivo and in vitro. Snail strongly repressed ESRP1 transcription through binding to the ESRP1 promoter in EOC cells. Furthermore, ESRP1 regulated the expression of CD44s. Down-regulated ESRP1 resulted in an isoform switching from CD44v to CD44s, which modulated epithelial-mesenchymal transition (EMT) program in EOC. Up-regulatin of ESRP1 was detected in mesenchymal to epithelial transition (MET) in vivo. Conclusions: ESRP1 regulates CD44 alternative splicing during the EMT process which plays an important role in EOC carcinogenesis. In addition, ESRP1 is associated with disease prognosis in EOC.

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Proline-rich protein 11 overexpression is associated with a more aggressive phenotype and poor overall survival in ovarian cancer patients

10.21203/rs.3.rs-35747/v2 ◽

2020 ◽

Author(s):

yu zhan ◽

xueyuan wu ◽

gang zheng ◽

jingjing jin ◽

chaofu li ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Curative Surgery ◽

Poor Overall Survival ◽

Expression Levels ◽

Prognostic Assessment ◽

Therapy Strategies ◽

Proline Rich Protein

Abstract Background: The proline-rich protein 11 (PRR11) is a newly identified oncogene associated with a poor prognosis in several human cancers. Nonetheless, research on its role in ovarian cancer (OC) remains largely understudied. Therefore, this study aims to evaluate the expression levels of PRR11 protein and its role in human ovarian cancer. Methods: Immunohistochemistry analysis was used to evaluate the expression levels of PRR11 protein in human samples obtained from 49 patients diagnosed with OC and subjected to curative surgery in the First Affiliated Hospital of Wenzhou Medical University between 2007 and 2015. Results: In total, 57.1% of the primary OC tumor tissue evaluated demonstrated overexpression of PRR11. Meanwhile, survival analysis showed that the overall survival (OS) of patients presenting overexpression of PRR11 was significantly lower than the OS of the patients with negative PRR11. In subsequent experiments, it was found that silencing the expression of PRR11 expression inhibited the proliferation of tumor cells and the migration of cells in vitro. Further, cells subjected to PRR11 knockdown exhibited a decrease in tumor growth in vivo. The downregulation of PRR11 was coupled with a decrease in N-cadherin and downregulation in the expression of early growth response protein 1 (EGR1).Conclusions: The findings suggest that PRR11 might be considered as a potential target for prognostic assessment and gene therapy strategies for patients diagnosed with OC.

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Antioxidant supplements promote tumor formation and growth and confer drug resistance in hepatocellular carcinoma by reducing intracellular ROS and induction of TMBIM1

Cell & Bioscience ◽

10.1186/s13578-021-00731-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Vanilla Xin Zhang ◽

Karen Man-Fong Sze ◽

Lo-Kong Chan ◽

Daniel Wai-Hung Ho ◽

Yu-Man Tsui ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatoma Cell ◽

Tumor Formation ◽

In Vitro Assays ◽

Migration And Invasion ◽

Intracellular Ros ◽

Antioxidant Supplements ◽

Sphere Formation

Abstract Background Controversy over the benefits of antioxidants supplements in cancers persists for long. Using hepatocellular carcinoma (HCC) as a model, we investigated the effects of exogenous antioxidants N-acetylcysteine (NAC) and glutathione (GSH) on tumor formation and growth. Methods Multiple mouse models, including diethylnitrosamine (DEN)-induced and Trp53KO/C-MycOE-induced HCC models, mouse hepatoma cell and human HCC cell xenograft models with subcutaneous or orthotopic injection were used. In vitro assays including ROS assay, colony formation, sphere formation, proliferation, migration and invasion, apoptosis, cell cycle assays were conducted. Western blot was performed for protein expression and RNA-sequencing to identify potential gene targets. Results In these multiple different mouse and cell line models, we observed that NAC and GSH promoted HCC tumor formation and growth, accompanied with significant reduction of intracellular reactive oxygen species (ROS) levels. Moreover, NAC and GSH promoted cancer stemness, and abrogated the tumor-suppressive effects of Sorafenib both in vitro and in vivo. Exogenous supplementation of NAC or GSH reduced the expression of NRF2 and GCLC, suggesting the NRF2/GCLC-related antioxidant production pathway might be desensitized. Using transcriptomic analysis to identify potential gene targets, we found that TMBIM1 was significantly upregulated upon NAC and GSH treatment. Both TCGA and in-house RNA-sequence databases showed that TMBIM1 was overexpressed in HCC tumors. Stable knockdown of TMBIM1 increased the intracellular ROS; it also abolished the promoting effects of the antioxidants in HCC cells. On the other hand, BSO and SSA, inhibitors targeting NAC and GSH metabolism respectively, partially abrogated the pro-oncogenic effects induced by NAC and GSH in vitro and in vivo. Conclusions Our data implicate that exogenous antioxidants NAC and GSH, by reducing the intracellular ROS levels and inducing TMBIM expression, promoted HCC formation and tumor growth, and counteracted the therapeutic effect of Sorafenib. Our study provides scientific insight regarding the use of exogenous antioxidant supplements in cancers.

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Proline-rich protein 11 overexpression is associated with a more aggressive phenotype and poor overall survival in ovarian cancer patients

10.21203/rs.3.rs-35747/v3 ◽

2020 ◽

Author(s):

yu zhan ◽

xueyuan wu ◽

gang zheng ◽

jingjing jin ◽

chaofu li ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Curative Surgery ◽

Poor Overall Survival ◽

Expression Levels ◽

Prognostic Assessment ◽

Therapy Strategies ◽

Proline Rich Protein

Abstract Background: The proline-rich protein 11 (PRR11) is a newly identified oncogene associated with a poor prognosis in several human cancers. Nonetheless, research on its role in ovarian cancer (OC) remains largely understudied. Therefore, this study aims to evaluate the expression levels of PRR11 protein and its role in human ovarian cancer. Methods: Immunohistochemistry analysis was used to evaluate the expression levels of PRR11 protein in human samples obtained from 49 patients diagnosed with OC and subjected to curative surgery in the First Affiliated Hospital of Wenzhou Medical University between 2007 and 2015. Results: In total, 57.1% of the primary OC tumor tissue evaluated demonstrated overexpression of PRR11. Meanwhile, survival analysis showed that the overall survival (OS) of patients presenting overexpression of PRR11 was significantly lower than the OS of the patients with negative PRR11. In subsequent experiments, it was found that silencing the expression of PRR11 expression inhibited the proliferation of tumor cells and the migration of cells in vitro. Further, cells subjected to PRR11 knockdown exhibited a decrease in tumor growth in vivo. The downregulation of PRR11 was coupled with a decrease in N-cadherin and downregulation in the expression of early growth response protein 1 (EGR1).Conclusions: The findings suggest that PRR11 might be considered as a potential target for prognostic assessment and gene therapy strategies for patients diagnosed with OC.

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LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

Cancers ◽

10.3390/cancers10080260 ◽

2018 ◽

Vol 10 (8) ◽

pp. 260 ◽

Cited By ~ 9

Author(s):

Qing Zhang ◽

Xiaonan Hou ◽

Bradley Evans ◽

Jamison VanBlaricom ◽

Saravut Weroha ◽

...

Keyword(s):

Ovarian Cancer ◽

Tumor Growth ◽

Cell Lines ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Migration And Invasion ◽

Ascites Formation ◽

Tgf Β1

Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer- and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.

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The polypeptide GALNT6 Displays Redundant Functions upon Suppression of its Closest Homolog GALNT3 in Mediating Aberrant O-Glycosylation, Associated with Ovarian Cancer Progression

International Journal of Molecular Sciences ◽

10.3390/ijms20092264 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2264 ◽

Cited By ~ 5

Author(s):

Razan Sheta ◽

Magdalena Bachvarova ◽

Elizabeth Macdonald ◽

Stephane Gobeil ◽

Barbara Vanderhyden ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Survival Rates ◽

Functional Redundancy ◽

Tumor Formation ◽

Migration And Invasion ◽

Gene Ablation

Epithelial ovarian cancer (EOC) represents the most lethal gynecologic malignancy; a better understanding of the molecular mechanisms associated with EOC etiology could substantially improve EOC management. Aberrant O-glycosylation in cancer is attributed to alteration of N-acetylgalactosaminyltransferases (GalNAc-Ts). Reports suggest a genetic and functional redundancy between GalNAc-Ts, and our previous data are indicative of an induction of GALNT6 expression upon GALNT3 suppression in EOC cells. We performed single GALNT3 and double GALNT3/T6 suppression in EOC cells, using a combination of the CRISPR-Cas9 system and shRNA-mediated gene silencing. The effect of single GALNT3 and double GALNT3/T6 inhibition was monitored both in vitro (on EOC cells roliferation, migration, and invasion) and in vivo (on tumor formation and survival of experimental animals). We confirmed that GALNT3 gene ablation leads to strong and rather compensatory GALNT6 upregulation in EOC cells. Moreover, double GALNT3/T6 suppression was significantly associated with stronger inhibitory effects on EOC cell proliferation, migration, and invasion, and accordingly displayed a significant increase in animal survival rates compared with GALNT3-ablated and control (Ctrl) EOC cells. Our data suggest a possible functional redundancy of GalNAc-Ts (GALNT3 and T6) in EOC, with the perspective of using both these enzymes as novel EOC biomarkers and/or therapeutic targets.

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