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1.
Cell Death Dis ; 10(3): 180, 2019 02 21.
Article in English | MEDLINE | ID: mdl-30792401

ABSTRACT

Potassium ion channels are critical in the regulation of cell motility. The acquisition of cell motility is an essential parameter of cancer metastasis. However, the role of K+ channels in cancer metastasis has been poorly studied. High expression of the hG1 gene, which encodes for Kv11.1 channel associates with good prognosis in estrogen receptor-negative breast cancer (BC). We evaluated the efficacy of the Kv11.1 activator NS1643 in arresting metastasis in a triple negative breast cancer (TNBC) mouse model. NS1643 significantly reduces the metastatic spread of breast tumors in vivo by inhibiting cell motility, reprogramming epithelial-mesenchymal transition via attenuation of Wnt/ß-catenin signaling and suppressing cancer cell stemness. Our findings provide important information regarding the clinical relevance of potassium ion channel expression in breast tumors and the mechanisms by which potassium channel activity can modulate tumor biology. Findings suggest that Kv11.1 activators may represent a novel therapeutic approach for the treatment of metastatic estrogen receptor-negative BC. Ion channels are critical factor for cell motility but little is known about their role in metastasis. Stimulation of the Kv11.1 channel suppress the metastatic phenotype in TNBC. This work could represent a paradigm-shifting approach to reducing mortality by targeting a pathway that is central to the development of metastases.


Subject(s)
ERG1 Potassium Channel/metabolism , Epithelial-Mesenchymal Transition , Triple Negative Breast Neoplasms/metabolism , Wnt Signaling Pathway/genetics , beta Catenin/metabolism , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Movement/drug effects , Cell Movement/genetics , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cresols/pharmacology , Cresols/therapeutic use , ERG1 Potassium Channel/genetics , Epithelial-Mesenchymal Transition/drug effects , Epithelial-Mesenchymal Transition/genetics , Female , Humans , MCF-7 Cells , Mice , Neoplasm Metastasis , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Transplantation, Heterologous , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/mortality , Triple Negative Breast Neoplasms/pathology , beta Catenin/antagonists & inhibitors , beta Catenin/genetics
2.
Biochem Biophys Res Commun ; 498(4): 1085-1092, 2018 04 15.
Article in English | MEDLINE | ID: mdl-29555478

ABSTRACT

Studies have shown that transforming acidic coiled-coil protein 3 (TACC3), a key component of centrosome-microtubule dynamic networks, is significantly associated with various types of human cancer. We have recently reported that high levels of TACC3 are found in breast cancer, lead to the accumulation of spontaneous DNA damage due to defective DNA damage response signaling, and confer cellular sensitivity to radiation and poly(ADP-ribose) polymerase (PARP) inhibitors. Although our study suggests a potential role of TACC3 as a biomarker in breast cancer detection and prediction of therapy outcome, its role as a therapeutic target in breast cancer is not well studied. In this study, we show that a small molecule TACC3 inhibitor, KHS101, suppresses cell growth, motility, epithelial-mesenchymal transition (EMT), and breast cancer cell stemness while it induces apoptotic cell death. Quantitative multiplexed proteomic analysis using tandem mass tags (TMTs) revealed that KHS101 alters multiple biological processes and signaling pathways, and significantly reduces the expression of mitotic kinases Aurora A and Polo-like kinase 1 (PLK1), which are closely associated with TACC3. Our findings therefore provide a new insight into the potential mechanisms of the action of KHS101 and suggest its possible use as a dual or multi-targeting mitotic inhibitor in breast cancer.


Subject(s)
Breast Neoplasms/drug therapy , Microtubule-Associated Proteins/antagonists & inhibitors , Thiazoles/pharmacology , Apoptosis , Aurora Kinase A/metabolism , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Movement , Cell Proliferation , Epithelial-Mesenchymal Transition , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Neoplasm Proteins/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Proteomics/methods , Proto-Oncogene Proteins/metabolism , Signal Transduction/drug effects , Thiazoles/therapeutic use , Polo-Like Kinase 1
3.
Anticancer Res ; 38(3): 1303-1310, 2018 03.
Article in English | MEDLINE | ID: mdl-29491053

ABSTRACT

BACKGROUND/AIM: Breast cancer is the most common malignant cancer type in women, and triple-negative breast cancer (TNBC) is an extremely aggressive subtype of breast cancer with poor prognosis rates. The present study investigated the antitumor effect of polo-like kinase 1 (PLK1) inhibitor in combination with the tankyrase-1 (TNKS1) inhibitor on TNBC cells. MATERIALS AND METHODS: We evaluated the antitumor effects of combination therapy with PLK1 and TNKS1 inhibitor using cell viability analysis, apoptosis assay and transwell assay for cell invasion and migration in TNBC cells. RESULTS: Combination treatment with PLK1 and TNKS1 inhibitors not only inhibited the invasion and migration capacity of TNBC cells, but also increased the apoptosis and cell death of TNBC cells. The viability of TNBC cells with low expression of ß-catenin and high expression of PLK1 was not affected by treatment with PLK1 inhibitor. However, the combination treatment with the TNKS1 inhibitor significantly decreased cell invasion and migration and increased apoptosis. CONCLUSION: Combination therapy of PLK1 and TNKS1 inhibitors may improve the therapeutic efficacy of the current treatment for TNBC.


Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Enzyme Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Tankyrases/antagonists & inhibitors , Triple Negative Breast Neoplasms/drug therapy , Apoptosis/drug effects , Apoptosis/genetics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/genetics , Cell Survival/drug effects , Cell Survival/genetics , Drug Synergism , Drug Therapy, Combination , Enzyme Inhibitors/pharmacology , Female , HeLa Cells , Humans , Kaplan-Meier Estimate , MCF-7 Cells , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , RNA Interference , Tankyrases/genetics , Tankyrases/metabolism , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism , Polo-Like Kinase 1
4.
Oncotarget ; 9(3): 3321-3337, 2018 Jan 09.
Article in English | MEDLINE | ID: mdl-29423049

ABSTRACT

Potassium ion (K+) channels have been recently found to play a critical role in cancer biology. Despite that pharmacologic manipulation of ion channels is recognized as an important therapeutic approach, very little is known about the effects of targeting of K+ channels in cancer. In this study, we demonstrate that use of the Kv11.1 K+ channel activator NS1643 inhibits tumor growth in an in vivo model of breast cancer. Tumors exposed to NS1643 had reduced levels of proliferation markers, high expression levels of senescence markers, increased production of ROS and DNA damage compared to tumors of untreated mice. Importantly, mice treated with NS1643 did not exhibit significant cardiac dysfunction. In conclusion, pharmacological stimulation of Kv11.1 activity produced arrested TNBC-derived tumor growth by generating DNA damage and senescence without significant side effects. We propose that use of Kv11.1 channels activators could be considered as a possible pharmacological strategy against breast tumors.

5.
Biochem Biophys Res Commun ; 496(2): 633-640, 2018 02 05.
Article in English | MEDLINE | ID: mdl-29355525

ABSTRACT

In spite of the push to identify modifiers of BRCAness, it still remains unclear how tumor suppressor BRCA1 is lost in breast cancers in the absence of genetic or epigenetic aberrations. Mounting evidence indicates that the transforming acidic coiled-coil 3 (TACC3) plays an important role in the centrosome-microtubule network during mitosis and gene expression, and that deregulation of TACC3 is associated with breast cancer. However, the molecular mechanisms by which TACC3 contributes to breast cancer development have yet to be elucidated. Herein, we found that high levels of TACC3 in human mammary epithelial cells can cause genomic instability possibly in part through destabilizing BRCA1. We also found that high levels of TACC3 inhibited the interaction between BRCA1 and BARD1, thus subsequently allowing the BARD1-uncoupled BRCA1 to be destabilized by ubiquitin-mediated proteosomal pathway. Moreover, there is an inverse correlation between TACC3 and BRCA1 expression in breast cancer tissues. Overall, our findings provide a new insight into the role of TACC3 in genomic instability and breast tumorigenesis.


Subject(s)
BRCA1 Protein/metabolism , Microtubule-Associated Proteins/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line , Female , Genomic Instability , Humans , Protein Interaction Maps , Protein Stability , Proteolysis , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitination
6.
Oncotarget ; 8(49): 86799-86815, 2017 Oct 17.
Article in English | MEDLINE | ID: mdl-29156836

ABSTRACT

BRCA1 is an important player in the DNA damage response signaling, and its deficiency results in genomic instability. A complete loss or significantly reduced BRCA1 protein expression is often found in sporadic breast cancer cases despite the absence of genetic or epigenetic aberrations, suggesting the existence of other regulatory mechanisms controlling BRCA1 protein expression. Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552. In addition, Rak deficiency confers cellular sensitivity to DNA damaging agents and poly(ADP-ribose) polymerase (PARP) inhibitors. Overall, our findings highlight a critical role of Rak in the maintenance of genomic stability, at least in part, through protecting BRCA1 and provide novel treatment strategies for patients with breast tumors lacking Rak.

7.
Biomed Res Int ; 2016: 2346585, 2016.
Article in English | MEDLINE | ID: mdl-27642590

ABSTRACT

Poly(ADP-ribose) polymerase (PARP) inhibitors have proven to be successful agents in inducing synthetic lethality in several malignancies. Several PARP inhibitors have reached clinical trial testing for treatment in different cancers, and, recently, Olaparib (AZD2281) has gained both United States Food and Drug Administration (USFDA) and the European Commission (EC) approval for use in BRCA-mutated advanced ovarian cancer treatment. The need to identify biomarkers, their interactions in DNA damage repair pathways, and their potential utility in identifying patients who are candidates for PARP inhibitor treatment is well recognized. In this review, we detail many of the biomarkers that have been investigated for their ability to predict both PARP inhibitor sensitivity and resistance in preclinical studies as well as the results of several clinical trials that have tested the safety and efficacy of different PARP inhibitor agents in BRCA and non-BRCA-mutated cancers.


Subject(s)
Ovarian Neoplasms/drug therapy , Poly(ADP-ribose) Polymerase Inhibitors/chemistry , Precision Medicine/methods , Animals , Biomarkers, Tumor/metabolism , Breast Neoplasms , Cell Line, Tumor , Clinical Trials as Topic , Drug Resistance, Neoplasm , Europe , Female , HeLa Cells , Humans , Male , Mice , Ovarian Neoplasms/enzymology , Phthalazines/chemistry , Piperazines/chemistry , United States , United States Food and Drug Administration
9.
Oncoscience ; 2(10): 847-8, 2015.
Article in English | MEDLINE | ID: mdl-26682275
10.
Biomed Res Int ; 2015: 420891, 2015.
Article in English | MEDLINE | ID: mdl-26356073

ABSTRACT

Gynecologic cancers are the unregulated growth of neoplastic cells that arise in the cervix, ovaries, fallopian tubes, uterus, vagina, and vulva. Although gynecologic cancers are characterized by different signs and symptoms, studies have shown that they share common risk factors, such as smoking, obesity, age, exposure to certain chemicals, infection with human immunodeficiency virus (HIV), and infection with human papilloma virus (HPV). Despite recent advancements in the preventative, diagnostic, and therapeutic interventions for gynecologic cancers, many patients still die as a result of metastasis and recurrence. Since mounting evidence indicates that the epithelial-mesenchymal transition (EMT) process plays an essential role in metastatic relapse of cancer, understanding the molecular aberrations responsible for the EMT and its underlying signaling should be given high priority in order to reduce cancer morbidity and mortality.


Subject(s)
Epithelial-Mesenchymal Transition/physiology , Genital Neoplasms, Female/pathology , Animals , Female , Genital Neoplasms, Female/virology , Gynecology/methods , HIV/pathogenicity , Humans , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/virology , Papillomaviridae/pathogenicity
11.
Cell Rep ; 10(12): 2055-68, 2015 Mar 31.
Article in English | MEDLINE | ID: mdl-25801032

ABSTRACT

Mutations and inactivation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) are observed in 15%-25% of cases of human T cell acute lymphoblastic leukemia (T-ALL). Pten deletion induces myeloproliferative disorders (MPDs), acute myeloid leukemia (AML), and/or T-ALL in mice. Previous studies attributed Pten-loss-related hematopoietic defects and leukemogenesis to excessive activation of phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling. Although inhibition of this signal dramatically suppresses the growth of PTEN-null T-ALL cells in vitro, treatment with inhibitors of this pathway does not cause a complete remission in vivo. Here, we report that focal adhesion kinase (Fak), a protein substrate of Pten, also contributes to T-ALL development in Pten-null mice. Inactivation of the FAK signaling pathway by either genetic or pharmacologic methods significantly sensitizes both murine and human PTEN-null T-ALL cells to PI3K/AKT/mTOR inhibition when cultured in vitro on feeder layer cells or a matrix and in vivo.


Subject(s)
Focal Adhesion Protein-Tyrosine Kinases/metabolism , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Animals , Humans , Leukemia/metabolism , Mice , Mice, Knockout , Signal Transduction/drug effects
12.
PLoS One ; 8(8): e70353, 2013.
Article in English | MEDLINE | ID: mdl-23936413

ABSTRACT

The third member of transforming acidic coiled-coil protein (TACC) family, TACC3, has been shown to be an important player in the regulation of centrosome/microtubule dynamics during mitosis and found to be deregulated in a variety of human malignancies. Our previous studies have suggested that TACC3 may be involved in cervical cancer progression and chemoresistance, and its overexpression can induce epithelial-mesenchymal transition (EMT) by activating the phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated protein kinases (ERKs) signal transduction pathways. However, the upstream mechanisms of TACC3-mediated EMT and its functional/clinical importance in human cervical cancer remain elusive. Epidermal growth factor (EGF) has been shown to be a potent inducer of EMT in cervical cancer and associated with tumor invasion and metastasis. In this study, we found that TACC3 is overexpressed in cervical cancer and can be induced upon EGF stimulation. The induction of TACC3 by EGF is dependent on the tyrosine kinase activity of the EGF receptor (EGFR). Intriguingly, depletion of TACC3 abolishes EGF-mediated EMT, suggesting that TACC3 is required for EGF/EGFR-driven EMT process. Moreover, Snail, a key player in EGF-mediated EMT, is found to be correlated with the expression of TACC3 in cervical cancer. Collectively, our study highlights a novel function for TACC3 in EGF-mediated EMT process and suggests that targeting of TACC3 may be an attractive strategy to treat cervical cancers driven by EGF/EGFR signaling pathways.


Subject(s)
Epidermal Growth Factor/pharmacology , Epithelial-Mesenchymal Transition/drug effects , Microtubule-Associated Proteins/metabolism , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathology , Cell Line, Tumor , ErbB Receptors/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Microtubule-Associated Proteins/genetics , Middle Aged , Snail Family Transcription Factors , Transcription Factors/metabolism , Uterine Cervical Neoplasms/genetics
13.
Cancer Lett ; 336(1): 24-33, 2013 Aug 09.
Article in English | MEDLINE | ID: mdl-23624299

ABSTRACT

Fine-tuned regulation of the centrosome/microtubule dynamics during mitosis is essential for faithful cell division. Thus, it is not surprising that deregulations in this dynamic network can contribute to genomic instability and tumorigenesis. Indeed, centrosome loss or amplification, spindle multipolarity and aneuploidy are often found in a majority of human malignancies, suggesting that defects in centrosome and associated microtubules may be directly or indirectly linked to cancer. Therefore, future research to identify and characterize genes required for the normal centrosome function and microtubule dynamics may help us gain insight into the complexity of cancer, and further provide new avenues for prognostic, diagnostics and therapeutic interventions. Members of the transforming acidic coiled-coil proteins (TACCs) family are emerging as important players of centrosome and microtubule-associated functions. Growing evidence indicates that TACCs are involved in the progression of certain solid tumors. Here, we will discuss our current understanding of the biological function of TACCs, their relevance to human cancer and possible implications for cancer management.


Subject(s)
Gene Expression Regulation, Neoplastic , Microtubule-Associated Proteins/metabolism , Neoplasms/genetics , Animals , Carrier Proteins/metabolism , Cell Transformation, Neoplastic , Centrosome/ultrastructure , Fetal Proteins/metabolism , Gene Expression Profiling , Humans , Microtubules/ultrastructure , Neoplasms/metabolism , Neoplasms/pathology , Nuclear Proteins/metabolism , Oncogenes , Tumor Suppressor Proteins/metabolism
14.
Cancer Lett ; 332(1): 63-73, 2013 May 10.
Article in English | MEDLINE | ID: mdl-23348690

ABSTRACT

Transforming acidic coiled-coil protein 3 (TACC3) is a member of the TACC family, essential for mitotic spindle dynamics and centrosome integrity during mitosis. Mounting evidence suggests that deregulation of TACC3 is associated with various types of human cancer. However, the molecular mechanisms by which TACC3 contributes to the development of cancer remain largely unknown. Here, we propose a novel mechanism by which TACC3 regulates epithelial-mesenchymal transition (EMT). By modulating the expression of TACC3, we found that overexpression of TACC3 leads to changes in cell morphology, proliferation, transforming capability, migratory/invasive behavior as well as the expression of EMT-related markers. Moreover, phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated protein kinases (ERKs) signaling pathways are critical for TACC3-mediated EMT process. Notably, depletion of TACC3 is sufficient to suppress EMT phenotype. Collectively, our findings identify TACC3 as a driver of tumorigenesis as well as an inducer of oncogenic EMT and highlight its overexpression as a potential therapeutic target for preventing EMT-associated tumor progression and invasion.


Subject(s)
Epithelial-Mesenchymal Transition , Extracellular Signal-Regulated MAP Kinases/metabolism , Microtubule-Associated Proteins/metabolism , Phosphatidylinositol 3-Kinase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Cell Movement , Cell Proliferation , Cell Shape , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Enzyme Activation , Epithelial-Mesenchymal Transition/drug effects , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/genetics , HEK293 Cells , HeLa Cells , Humans , Microtubule-Associated Proteins/genetics , Neoplasm Invasiveness , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/genetics , RNA Interference , Signal Transduction/drug effects , Time Factors , Transfection , beta Catenin/metabolism
15.
Biochem Res Int ; 2012: 268504, 2012.
Article in English | MEDLINE | ID: mdl-23213529
16.
Biochem Res Int ; 2012: 195903, 2012.
Article in English | MEDLINE | ID: mdl-22852086

ABSTRACT

Mitosis is tightly regulated and any errors in this process often lead to aneuploidy, genomic instability, and tumorigenesis. Deregulation of mitotic kinases is significantly associated with improper cell division and aneuploidy. Because of their importance during mitosis and the relevance to cancer, mitotic kinase signaling has been extensively studied over the past few decades and, as a result, several mitotic kinase inhibitors have been developed. Despite promising preclinical results, targeting mitotic kinases for cancer therapy faces numerous challenges, including safety and patient selection issues. Therefore, there is an urgent need to better understand the molecular mechanisms underlying mitotic kinase signaling and its interactive network. Increasing evidence suggests that tumor suppressor p53 functions at the center of the mitotic kinase signaling network. In response to mitotic spindle damage, multiple mitotic kinases phosphorylate p53 to either activate or deactivate p53-mediated signaling. p53 can also regulate the expression and function of mitotic kinases, suggesting the existence of a network of mutual regulation, which can be positive or negative, between mitotic kinases and p53 signaling. Therefore, deciphering this regulatory network will provide knowledge to overcome current limitations of targeting mitotic kinases and further improve the results of targeted therapy.

17.
Int J Proteomics ; 20112011 Jan 01.
Article in English | MEDLINE | ID: mdl-21886869

ABSTRACT

Technological and scientific innovations over the last decade have greatly contributed to improved diagnostics, predictive models, and prognosis among cancers affecting women. In fact, an explosion of information in these areas has almost assured future generations that outcomes in cancer will continue to improve. Herein we discuss the current status of breast, cervical, and ovarian cancers as it relates to screening, disease diagnosis, and treatment options. Among the differences in these cancers, it is striking that breast cancer has multiple predictive tests based upon tumor biomarkers and sophisticated, individualized options for prescription therapeutics while ovarian cancer lacks these tools. In addition, cervical cancer leads the way in innovative, cancer-preventative vaccines and multiple screening options to prevent disease progression. For each of these malignancies, emerging proteomic technologies based upon mass spectrometry, stable isotope labeling with amino acids, high-throughput ELISA, tissue or protein microarray techniques, and click chemistry in the pursuit of activity-based profiling can pioneer the next generation of discovery. We will discuss six of the latest techniques to understand proteomics in cancer and highlight research utilizing these techniques with the goal of improvement in the management of women's cancers.

18.
Cancer Res ; 71(20): 6524-34, 2011 Oct 15.
Article in English | MEDLINE | ID: mdl-21852383

ABSTRACT

Genome-wide sequencing studies in breast cancer have recently identified frequent mutations in the zinc finger protein 668 (ZNF668), the function of which is undefined. Here, we report that ZNF668 is a nucleolar protein that physically interacts with and regulates p53 and its negative regulator MDM2. Through MDM2 binding, ZNF668 regulated autoubiquitination of MDM2 and its ability to mediate p53 ubiquitination and degradation. ZNF668 deficiency also impaired DNA damage-induced stabilization of p53. RNA interference-mediated knockdown of ZNF668 was sufficient to transform normal mammary epithelial cells. ZNF668 effectively suppressed breast cancer cell proliferation in vitro and tumorigenicity in vivo. Taken together, our studies identify ZNF668 as a novel breast tumor suppressor gene that functions in regulating p53 stability.


Subject(s)
Breast Neoplasms/metabolism , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Proteins/metabolism , Zinc Fingers , Amino Acid Sequence , Breast/metabolism , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic/metabolism , DNA Damage , Female , Humans , Molecular Sequence Data , Nuclear Proteins/metabolism , Proto-Oncogene Proteins c-mdm2/metabolism , RNA Interference , Tumor Suppressor Proteins/genetics , Ubiquitination
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