scholarly journals UBE2O promotes the proliferation, EMT and stemness properties of breast cancer cells through the UBE2O/AMPKα2/mTORC1-MYC positive feedback loop

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xu Liu ◽  
Fei Ma ◽  
Chunxiao Liu ◽  
Kaiyuan Zhu ◽  
Wenjie Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Positive Feedback ◽  
Feedback Loop ◽  
In Vitro Assays ◽  
Positive Feedback Loop ◽  
Ubiquitin Conjugating Enzyme ◽  
Mesenchymal Transformation ◽  
Conjugating Enzyme

AbstractUbiquitin-conjugating enzyme E2O (UBE2O) is a large E2 ubiquitin-conjugating enzyme that possesses both E2 and E3 ligase activities. Ectopic UBE2O overexpression is associated with a variety of human diseases, especially cancers. However, the expression profile and functional biology of UBE2O in human breast cancer (BC) remain unclear. In this study, we found that UBE2O was significantly overexpressed in human BC tissues and cells. Patients with high UBE2O expression tended to have a high risk of metastasis and poor prognosis. In vitro assays revealed that UBE2O promoted BC cell proliferation and epithelial–mesenchymal transformation (EMT) and endowed BC cells with cancer stemness properties (CSPs). UBE2O knockdown in MDA-MB-231 cells suppressed tumour growth and lung metastasis in MDA-MB-231 xenograft mouse models. Mechanistically, UBE2O functioned as a ubiquitin enzyme of AMPKα2, promoting its ubiquitination and degradation and thus activating the mTORC1 signal pathway and contributing to BC oncogenesis and metastasis. Furthermore, as a downstream factor of the UBE2O/AMPKα2/mTORC1 axis, the oncoprotein MYC transcriptionally promoted UBE2O and formed a positive feedback loop in human BC. Collectively, our study demonstrated that UBE2O/AMPKα2/mTORC1-MYC forms a positive feedback loop in human BC cells that regulates BC cell proliferation and EMT and endows BC cells with CSPs.

Long non-coding RNA HCG18 promotes malignant phenotypes of breast cancer (BC) cells by HCG18/miR-103a-3p/UBE2O/mTORC1/HIF-1α positive feedback loop

2021 ◽  
Author(s):  
Xu Liu ◽  
Kun Qiao ◽  
Kaiyuan Zhu ◽  
Xianglan Li ◽  
Chunbo Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Bioinformatic Analysis ◽  
In Vitro Assays ◽  
Luciferase Reporter ◽  
Regulatory Relationship ◽  
Positive Feedback Loop

Abstract Background: In recent years, a growing number of studies have reported that long non-coding RNAs (LncRNAs) play crucial roles in breast cancer (BC) progression and metastasis. Another study group of our research center reported that LncRNA HCG18 was one of the 30 upregulated lncRNAs in BC tissues related to normal tissues in TCGA database. However, the exactly biological roles of HCG18 in BC remains unclear. Method: qRT-PCR was used to detect the expression profile of HCG18 in BC tissues and cell lines. In vitro assays were used to evaluate the pro-tumor function of HCG18 in BC cells. Animal study were used to explore the role of HCG18 in vivo. Bioinformatic analysis, dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and Chromatin Immunoprecipitation (ChIP) assays were used to investigate the regulatory relationship of HCG18, miR-103a-3p, UBE2O in BC. Results: HCG18 was upregulated in BC tissues and cells, and BC patients with high HCG18 expression tended to have poor prognosis. HCG18 could promote BC cells proliferation, invasion and provided BC cells with tumor stemness properties (CSPs) in vitro and facilitate tumor growth and lung metastasis in vivo. In terms of mechanism, HCG18 functioned as a miRNA sponge which positively regulated the expression of Ubiquitin-conjugating enzyme E2O (UBE2O) by sponging miR-103a-3p and our previous research achievement have already verified UBE2O could promote malignant phenotypes of BC cells through UBE2O/AMPKα2/mTORC1 axis. Furthermore, as a downstream target of HCG18/miR-103a-3p/UBE2O/mTORC1 axis, HIF-1α transcriptionally promoted HCG18 expression and then formed a positive feedback loop in BC. Conclusion: HCG18 played an oncogenic role in BC and it might serve as a prognostic biomarker and a potential therapeutic target for BC treatment.

scholarly journals CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 contributes to prostate carcinogenesis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jin-Chun Qi ◽  
Zhan Yang ◽  
Tao Lin ◽  
Long Ma ◽  
Ya-Xuan Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcriptional Activation ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Biological Effects ◽  
Therapeutic Benefit ◽  
Loss Of Function ◽  
Positive Feedback Loop

Abstract Background Both E2F transcription factor and cyclin-dependent kinases (CDKs), which increase or decrease E2F activity by phosphorylating E2F or its partner, are involved in the control of cell proliferation, and some circRNAs and miRNAs regulate the expression of E2F and CDKs. However, little is known about whether dysregulation among E2Fs, CDKs, circRNAs and miRNAs occurs in human PCa. Methods The expression levels of CDK13 in PCa tissues and different cell lines were determined by quantitative real-time PCR and Western blot analysis. In vitro and in vivo assays were preformed to explore the biological effects of CDK13 in PCa cells. Co-immunoprecipitation anlysis coupled with mass spectrometry was used to identify E2F5 interaction with CDK13. A CRISPR-Cas9 complex was used to activate endogenous CDK13 and circCDK13 expression. Furthermore, the mechanism of circCDK13 was investigated by using loss-of-function and gain-of-function assays in vitro and in vivo. Results Here we show that CDK13 is significantly upregulated in human PCa tissues. CDK13 depletion and overexpression in PCa cells decrease and increase, respectively, cell proliferation, and the pro-proliferation effect of CDK13 is strengthened by its interaction with E2F5. Mechanistically, transcriptional activation of endogenous CDK13, but not the forced expression of CDK13 by its expression vector, remarkably promotes E2F5 protein expression by facilitating circCDK13 formation. Further, the upregulation of E2F5 enhances CDK13 transcription and promotes circCDK13 biogenesis, which in turn sponges miR-212-5p/449a and thus relieves their repression of the E2F5 expression, subsequently leading to the upregulation of E2F5 expression and PCa cell proliferation. Conclusions These findings suggest that CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 is responsible for PCa development. Targeting this newly identified regulatory axis may provide therapeutic benefit against PCa progression and drug resistance.

The Wnt/β-catenin/VASP positive feedback loop drives cell proliferation and migration in breast cancer

Oncogene ◽  
2019 ◽  
Vol 39 (11) ◽  
pp. 2258-2274 ◽  
Author(s):  
Kai Li ◽  
Jingwei Zhang ◽  
Yihao Tian ◽  
Yanqi He ◽  
Xiaolong Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Positive Feedback Loop ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

scholarly journals Long Noncoding RNA HCG18 Promotes Malignant Phenotypes of Breast Cancer Cells via the HCG18/miR-103a-3p/UBE2O/mTORC1/HIF-1α–Positive Feedback Loop

2021 ◽  
Vol 9 ◽  
Author(s):  
Xu Liu ◽  
Kun Qiao ◽  
Kaiyuan Zhu ◽  
Xianglan Li ◽  
Chunbo Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Positive Feedback ◽  
Noncoding Rna ◽  
Feedback Loop ◽  
Hypoxia Inducible Factor ◽  
The Cancer Genome Atlas ◽  
Positive Feedback Loop ◽  
Downstream Target

In recent years, an increasing number of studies have reported that long noncoding RNAs (lncRNAs) play crucial roles in breast cancer (BC) progression and metastasis. Another study group of our research center reported that lncRNA HCG18 was one of the 30 upregulated lncRNAs in BC tissues compared with normal tissues in The Cancer Genome Atlas database. However, the exact biological roles of HCG18 in BC remain unclear. In this study, we demonstrated that HCG18 is significantly upregulated in BC tissues and cells and that BC patients with high HCG18 expression tend to have poor prognosis. In vitro assays indicated that HCG18 promotes BC cell proliferation and invasion and endows BC cells with cancer stemness properties. In vivo assays revealed that reducing HCG18 expression in the BC cell line MDA-MB-231 markedly decreased tumor growth and lung metastasis in xenograft mouse models. In terms of mechanism, we found that HCG18 positively regulated the expression of BC-related ubiquitin-conjugating enzyme E2O (UBE2O) by sponging miR-103a-3p, and our previous research verified that UBE2O could promote the malignant phenotypes of BC cells through the UBE2O/AMPKα2/mTORC1 axis. Furthermore, as a downstream target of the HCG18/miR-103a-3p/UBE2O/mTORC1 axis, hypoxia-inducible factor 1α transcriptionally promoted HCG18 expression and then formed a positive feedback loop in BC. Taken together, these results confirm that HCG18 plays an oncogenic role in BC and might serve as a prognostic biomarker and a potential therapeutic target for BC treatment.

scholarly journals circFAM73A Promotes Cancer Stem Cell-like Properties of Gastric Cancer Through miR-490-3p/HMGA2 Positive Feedback and HNRNPK-mediated β-catenin Stabilization.

2020 ◽  
Author(s):  
Yiwen Xia ◽  
Jialun Lv ◽  
Tianlu Jiang ◽  
Bowen Li ◽  
Zhongyuan He ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Cisplatin Resistance ◽  
Circular Rnas ◽  
Small Subset ◽  
Positive Feedback Loop

Abstract Background: Circular RNAs (circRNAs) have emerged as a new subclass of regulatory RNAs that exert critical roles in various cancers. Cancer stem cells (CSCs), a small subset of cancer cells, are believed to possess the capacities to initiate tumorigenesis and promote progression. Although accumulating evidences have suggested that cells with CSC-like properties are crucial for the malignance process of gastric cancer (GC), it remains inexplicit whether circRNAs are interrelated with the acquisition of CSC-like properties in GC.Methods: circFAM73A expression was analyzed by GEO datasets and verified in GC samples. The role of circFAM73A on GC cell proliferation, migration, cisplatin resistance and CSC-like properties were determined by a series of functional experiment both in vitro and in vivo. RNA pull down was used to explore the miRNAs and proteins binding to circFAM73A. Bioinformatic analysis and experimental verification confirmed the downstream of circFAM73A. The regulation of HMGA2 on circFAM73A was verified by ChIP and RIP assays.Results: Elevated circFAM73A expression was confirmed in GC tissues and higher circFAM73A predicts poor prognosis of GC patients. The upregulation of circFAM73A enhanced CSC-like properties in GC, thus, exerting the facilitating role on cell proliferation, migration and cisplatin resistance. Mechanistically, circFAM73A promoted GC malignancy by regulating miR-490-3p/HMGA2 in a positive feedback loop and recruiting HNRNPK to facilitate β-catenin stabilization. Moreover, HMGA2 further enhanced E2F1 and HNRNPL activity, which in turn promotes circFAM73A expression.Conclusions: Our work demonstrates the crucial role of circFAM73A on GC CSC-like properties and uncovers a positive feedback loop on circFAM73A regulation that leads to the progression of gastric cancer, which may provide a new insight for circRNA-based diagnostic and therapeutic strategies.

scholarly journals A Positive Feedback Loop of Long Noncoding RNA LINC00152 and KLF5 Facilitates Breast Cancer Growth

2021 ◽  
Vol 11 ◽  
Author(s):  
Qiang Li ◽  
Xiao Wang ◽  
Liheng Zhou ◽  
Mingyun Jiang ◽  
Guansheng Zhong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Positive Feedback ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Feedback Loop ◽  
Clinical Value ◽  
Survival Prognosis ◽  
Aberrant Expression ◽  
Positive Feedback Loop

The long noncoding RNA (lncRNA) LINC00152, also known as CYTOR, displays aberrant expression in various cancers. However, its clinical value and functional mechanisms in breast cancer remain insufficiently understood. Our study found that LINC00152 is significantly upregulated in breast cancer, and that it acts as an indicator of poor survival prognosis. Further studies revealed that LINC00152 knockdown suppresses cell proliferation and tumorigenicity in vitro and in vivo. Mechanistic analyses demonstrated that LINC00152 directly binds to KLF5 protein and increases KLF5 stability. Moreover, LINC00152 is also a KLF5-responsive lncRNA, and KLF5 activates LINC00152 transcription by directly binding to its promoter. Our study suggests that LINC00152 promotes tumor progression by interacting with KLF5. LINC00152 may be a valuable prognostic predictor for breast cancer, and the positive feedback loop of LINC00152-KLF5 could be a therapeutic target in pharmacological strategies.

scholarly journals Methylation-mediated silencing of miR-133a-3p promotes breast cancer cell migration and stemness via miR-133a-3p/MAML1/DNMT3A positive feedback loop

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Wanyue Shi ◽  
Tingting Tang ◽  
Xinping Li ◽  
Siwei Deng ◽  
Ruiyi Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Positive Feedback ◽  
Breast Cancer Cells ◽  
Feedback Loop ◽  
Positive Feedback Loop

Abstract Background miR-133a-3p has been recently discovered to be down-regulated in various human malignancies, including breast cancer, and reduced miR-133a-3p levels have been significantly associated with breast cancer cell growth and invasion. However, the regulatory mechanisms leading to abnormal expression of miR-133a-3p in breast cancer remain obscure. Methods qRT-PCR was applied to detect the expression of miR-133a-3p in breast cancer tissues and cell lines. Bisulfite sequencing was used to detect the degree of methylation of the miR-133a-3p promoter. The effects of miR-133a-3p on breast cancer in vitro were examined by cell proliferation assay, transwell assay, flow cytometry, and western blotting. Bioinformatic analysis, dual-luciferase assay and RIP assay were employed to identify the interaction between miR-133a-3p and MAML1. A xenograft model was used to show the metastasis of breast cancer cells. Results We confirmed that miR-133a-3p was silenced by DNA hypermethylation in breast cancer cell lines and tissues, which predicted poor prognosis in breast cancer patients, and reducing miR-133a-3p expression led to a significant increase in the migration, invasion, proliferation, and stemness of breast cancer cells in vitro. Mastermind-like transcriptional coactivator 1 (MAML1) was confirmed to be a target of miR-133a-3p involved in regulating breast cancer metastasis both in vitro and in vivo. Moreover, a series of investigations indicated that MAML1 initiated a positive feedback loop, which could up-regulate DNA methyltransferase 3A (DNMT3A) to promote hypermethylation of the miR-133a-3p promoter. Conclusion Taken together, our findings revealed a novel miR-133a-3p/MAML1/DNMT3A positive feedback loop in breast cancer cells, which may become a potential therapeutic target for breast cancer.

scholarly journals IRE1α Expedites the Progression of Castration-Resistant Prostate Cancers via the Positive Feedback Loop of IRE1α/IL-6/AR

2021 ◽  
Vol 11 ◽  
Author(s):  
Fan Yang ◽  
Chong Yuan ◽  
Dan Wu ◽  
Jing Zhang ◽  
Xingchun Zhou
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Castration Resistant Prostate Cancer ◽  
Positive Feedback Loop ◽  
Castration Resistant ◽  
Prostate Cancers

Castration-resistant prostate cancer (CRPC) is the lethal form of prostate cancer (PCa), and the underlying molecular mechanism has not been fully elucidated. Inositol requiring enzyme 1 alpha (IRE1α), a key regulator of unfolded protein response (UPR), is intimately associated with PCa progression. However, whether IRE1α is implicated in CRPC development remains unknown. Here, we showed that IRE1α expression was significantly increased in CRPC tissues and high-grade PCa tissues. Overexpression of IRE1α promoted PCa cell proliferation under the androgen deficiency condition in vitro and in vivo. Mechanistically, increased IRE1α expression induced IL-6 secretion via the IRE1α/XBP-1s signal pathway. IRE1α-induced IL-6 activated androgen receptor (AR), and the activation of AR by IL-6, in turn, promoted IRE1α expression. IRE1α formed a positive feedback loop with IL-6 and AR to promote prostate cancer cell proliferation under the androgen-deficient condition. In clinical PCa samples, high IRE1α expression correlated with elevated IL-6 and increased PSA expression. Our findings demonstrated a novel mechanism of CRPC progression and suggest targeting IRE1α may be a potential target for the prevention and treatment of CRPC.

scholarly journals CircFAM73A promotes the cancer stem cell-like properties of gastric cancer through the miR-490-3p/HMGA2 positive feedback loop and HNRNPK-mediated β-catenin stabilization

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yiwen Xia ◽  
Jialun Lv ◽  
Tianlu Jiang ◽  
Bowen Li ◽  
Ying Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Cisplatin Resistance ◽  
Circular Rnas ◽  
Small Subset ◽  
Positive Feedback Loop

Abstract Background Circular RNAs (circRNAs) have emerged as a new subclass of regulatory RNAs that play critical roles in various cancers. Cancer stem cells (CSCs), a small subset of cancer cells, are believed to possess the capacities to initiate tumorigenesis and promote progression. Although accumulating evidence has suggested that cells with CSC-like properties are crucial for the malignancy of gastric cancer (GC), it remains unclear whether circRNAs are related to the acquisition of CSC-like properties in GC. Methods CircFAM73A expression was analyzed by GEO datasets and verified in GC samples. The roles of circFAM73A in GC cell proliferation, migration, cisplatin resistance, and CSC-like properties were determined by a series of functional experiments both in vitro and in vivo. RNA pulldown was used to explore the miRNAs and proteins binding to circFAM73A. Bioinformatic analysis and experimental verification confirmed the downstream targets of circFAM73A. The regulation of circFAM73A by HMGA2 was verified by ChIP and RIP assays. Results Elevated circFAM73A expression was confirmed in GC tissues, and higher circFAM73A predicted poor prognosis in GC patients. The upregulation of circFAM73A enhanced CSC-like properties in GC, thus facilitating cell proliferation, migration, and cisplatin resistance. Mechanistically, circFAM73A promoted GC malignancy by regulating miR-490-3p/HMGA2 in a positive feedback loop and recruiting HNRNPK to facilitate β-catenin stabilization. Moreover, HMGA2 further enhanced E2F1 and HNRNPL activity, which in turn promoted circFAM73A expression. Conclusions Our work demonstrates the crucial role of circFAM73A in the CSC-like properties of GC and uncovers a positive feedback loop in circFAM73A regulation that leads to the progression of gastric cancer, which may provide new insights into circRNA-based diagnostic and therapeutic strategies.

scholarly journals A positive-feedback loop between HBx and ALKBH5 promotes hepatocellular carcinogenesis

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Siming Qu ◽  
Li Jin ◽  
Hanfei Huang ◽  
Jie Lin ◽  
Weiwu Gao ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Hbv Infection ◽  
Cell Counting ◽  
Regulation Mechanism ◽  
Dependent Manner ◽  
Liver Carcinogenesis ◽  
Nude Mouse Model ◽  
Positive Feedback Loop

Abstract Background Hepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people. Methods The expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells. Result ALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells’ growth and migration in vitro and in vivo. Conclusions HBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.

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