scholarly journals Tumor Suppressive Effects of miR-124 and Its Function in Neuronal Development

2021 ◽  
Vol 22 (11) ◽  
pp. 5919
Author(s):  
Rikako Sanuki ◽  
Tomonori Yamamura
Keyword(s):  
Target Genes ◽  
Neuronal Development ◽  
Epithelial Mesenchymal Transition ◽  
Cell Lineage ◽  
Suppressive Effect ◽  
Breast Cancers ◽  
Mesenchymal Transition ◽  
Cell Metastasis ◽  
Wide Range ◽  
Cancer Types

MicroRNA-124 (miR-124) is strongly expressed in neurons, and its expression increases as neurons mature. Through DNA methylation in the miR-124 promoter region and adsorption of miR-124 by non-coding RNAs, miR-124 expression is known to be reduced in many cancer cells, especially with high malignancy. Recently, numerous studies have focused on miR-124 due to its promising tumor-suppressive effects; however, the overview of their results is unclear. We surveyed the tumor-suppressive effect of miR-124 in glial cell lineage cancers, which are the most frequently reported cancer types involving miR-124, and in lung, colon, liver, stomach, and breast cancers, which are the top five causes of cancer death. Reportedly, miR-124 not only inhibits proliferation and accelerates apoptosis, but also comprehensively suppresses tumor malignant transformation. Moreover, we found that miR-124 exerts its anti-tumor effects by regulating a wide range of target genes, most notably STAT3 and EZH2. In addition, when compared to the original role of miR-124 in neuronal development, we found that the miR-124 target genes that contribute to neuronal maturation share similarities with genes that cause cancer cell metastasis and epithelial-mesenchymal transition. We believe that the two apparently unrelated fields, cancer and neuronal development, can bring new discoveries to each other through the study of miR-124.

scholarly journals Interplay between miRNAs and host genes and their role in cancer

2019 ◽  
Vol 18 (4) ◽  
pp. 255-266 ◽  
Author(s):  
Baohong Liu ◽  
Yu Shyr ◽  
Jianping Cai ◽  
Qi Liu
Keyword(s):  
Tumor Suppressors ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Fine Tuning ◽  
Data Sets ◽  
Protein Coding ◽  
Mesenchymal Transition ◽  
Damage Repair ◽  
Cancer Types ◽  
Host Genes

Abstract MicroRNAs (miRNAs) are small endogenous non-coding functional RNAs that post-transcriptionally regulate gene expression. They play essential roles in nearly all biological processes including cell development and differentiation, DNA damage repair, cell death as well as intercellular communication. They are highly involved in cancer, acting as tumor suppressors and/or promoters to modulate cell proliferation, epithelial-mesenchymal transition and tumor invasion and metastasis. Recent studies have shown that more than half of miRNAs are located within protein-coding or non-coding genes. Intragenic miRNAs and their host genes either share the promoter or have independent transcription. Meanwhile, miRNAs work as partners or antagonists of their host genes by fine-tuning their target genes functionally associated with host genes. This review outlined the complicated relationship between intragenic miRNAs and host genes. Focusing on miRNAs known as oncogenes or tumor suppressors in specific cancer types, it studied co-expression relationships between these miRNAs and host genes in the cancer types using TCGA data sets, which validated previous findings and revealed common, tumor-specific and even subtype-specific patterns. These observations will help understand the function of intragenic miRNAs and further develop miRNA therapeutics in cancer.

scholarly journals Heat Shock Factor Hsf1 Cooperates with ErbB2 (Her2/Neu) Protein to Promote Mammary Tumorigenesis and Metastasis

2012 ◽  
Vol 287 (42) ◽  
pp. 35646-35657 ◽  
Author(s):  
Caixia Xi ◽  
Yanzhong Hu ◽  
Phillip Buckhaults ◽  
Demetrius Moskophidis ◽  
Nahid F. Mivechi
Keyword(s):  
Heat Shock ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Mammary Epithelial Cells ◽  
Mammary Tumorigenesis ◽  
Metastatic Breast ◽  
Inhibitory Effect ◽  
Heat Shock Factor ◽  
Breast Cancers ◽  
Mesenchymal Transition

ErbB2/Neu oncogene is overexpressed in 25% of invasive/metastatic breast cancers. We have found that deletion of heat shock factor Hsf1 in mice overexpressing ErbB2/Neu significantly reduces mammary tumorigenesis and metastasis. Hsf1+/−ErbB2/Neu+ tumors exhibit reduced cellular proliferative and invasive properties associated with reduced activated ERK1/2 and reduced epithelial-mesenchymal transition (EMT). Hsf1+/+Neu+ mammary epithelial cells exposed to TGFβ show high levels of ERK1/2 activity and EMT; this is associated with reduced expression of E-cadherin and increased expression of Slug and vimentin, a mesenchymal marker. In contrast, Hsf1−/−Neu+ or Hsf1+/+Neu+ cells do not exhibit activated ERK1/2 and show reduced EMT in the presence of TGFβ. The ineffective activation of the RAS/RAF/MEK/ERK1/2 signaling pathway in cells with reduced levels of HSF1 is due to the low levels of HSP90 in complex with RAF1 that are required for RAF1 stability and maturation. These results indicate a powerful inhibitory effect conferred by HSF1 downstream target genes in the inhibition of ErbB2-induced breast cancers in the absence of the Hsf1 gene.

scholarly journals RNA-Based TWIST1 Inhibition via Dendrimer Complex to Reduce Breast Cancer Cell Metastasis

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
James Finlay ◽  
Cai M. Roberts ◽  
Gina Lowe ◽  
Joana Loeza ◽  
John J. Rossi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Survival Rates ◽  
The United States ◽  
Cellular Migration ◽  
Migration And Invasion ◽  
Breast Cancers ◽  
Mesenchymal Transition

Breast cancer is the leading cause of cancer-related deaths among women in the United States, and survival rates are lower for patients with metastases and/or triple-negative breast cancer (TNBC; ER, PR, and Her2 negative). Understanding the mechanisms of cancer metastasis is therefore crucial to identify new therapeutic targets and develop novel treatments to improve patient outcomes. A potential target is the TWIST1 transcription factor, which is often overexpressed in aggressive breast cancers and is a master regulator of cellular migration through epithelial-mesenchymal transition (EMT). Here, we demonstrate an siRNA-based TWIST1 silencing approach with delivery using a modified poly(amidoamine) (PAMAM) dendrimer. Our results demonstrate that SUM1315 TNBC cells efficiently take up PAMAM-siRNA complexes, leading to significant knockdown of TWIST1 and EMT-related target genes. Knockdown lasts up to one week after transfection and leads to a reduction in migration and invasion, as determined by wound healing and transwell assays. Furthermore, we demonstrate that PAMAM dendrimers can deliver siRNA to xenograft orthotopic tumors and siRNA remains in the tumor for at least four hours after treatment. These results suggest that further development of dendrimer-based delivery of siRNA for TWIST1 silencing may lead to a valuable adjunctive therapy for patients with TNBC.

scholarly journals Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 714 ◽  
Author(s):  
Rama Soundararajan ◽  
Jared Fradette ◽  
Jessica Konen ◽  
Stacy Moulder ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Treatment Options ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Breast Cancers ◽  
Mesenchymal Transition ◽  
Cancer Types

Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors.

scholarly journals The Context-Dependent Impact of Integrin-Associated CD151 and Other Tetraspanins on Cancer Development and Progression: A Class of Versatile Mediators of Cellular Function and Signaling, Tumorigenesis and Metastasis

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2005
Author(s):  
Sonia Erfani ◽  
Hui Hua ◽  
Yueyin Pan ◽  
Binhua P. Zhou ◽  
Xiuwei H. Yang
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Wide Spectrum ◽  
Tumor Development ◽  
Cell Lineage ◽  
Integral Membrane Proteins ◽  
Multiple Cancer ◽  
Mesenchymal Transition ◽  
Current Review ◽  
Cancer Types

As a family of integral membrane proteins, tetraspanins have been functionally linked to a wide spectrum of human cancers, ranging from breast, colon, lung, ovarian, prostate, and skin carcinomas to glioblastoma. CD151 is one such prominent member of the tetraspanin family recently suggested to mediate tumor development, growth, and progression in oncogenic context- and cell lineage-dependent manners. In the current review, we summarize recent advances in mechanistic understanding of the function and signaling of integrin-associated CD151 and other tetraspanins in multiple cancer types. We also highlight emerging genetic and epigenetic evidence on the intrinsic links between tetraspanins, the epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), and the Wnt/β-catenin pathway, as well as the dynamics of exosome and cellular metabolism. Finally, we discuss the implications of the highly plastic nature and epigenetic susceptibility of CD151 expression, function, and signaling for clinical diagnosis and therapeutic intervention for human cancer.

scholarly journals A pan-cancer analysis of CpG Island gene regulation reveals extensive plasticity within Polycomb target genes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yueyuan Zheng ◽  
Guowei Huang ◽  
Tiago C. Silva ◽  
Qian Yang ◽  
Yan-Yi Jiang ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Cpg Island ◽  
Regulatory Control ◽  
Cancer Type ◽  
Systematic Analysis ◽  
Mesenchymal Transition ◽  
Genetic Perturbations ◽  
Cancer Types

AbstractCpG Island promoter genes make up more than half of human genes, and a subset regulated by Polycomb-Repressive Complex 2 (PRC2+-CGI) become DNA hypermethylated and silenced in cancer. Here, we perform a systematic analysis of CGI genes across TCGA cancer types, finding that PRC2+-CGI genes are frequently prone to transcriptional upregulation as well. These upregulated PRC2+-CGI genes control important pathways such as Epithelial-Mesenchymal Transition (EMT) and TNFα-associated inflammatory response, and have greater cancer-type specificity than other CGI genes. Using publicly available chromatin datasets and genetic perturbations, we show that transcription factor binding sites (TFBSs) within distal enhancers underlie transcriptional activation of PRC2+-CGI genes, coinciding with loss of the PRC2-associated mark H3K27me3 at the linked promoter. In contrast, PRC2-free CGI genes are predominantly regulated by promoter TFBSs which are common to most cancer types. Surprisingly, a large subset of PRC2+-CGI genes that are upregulated in one cancer type are also hypermethylated/silenced in at least one other cancer type, underscoring the high degree of regulatory plasticity of these genes, likely derived from their complex regulatory control during normal development.

scholarly journals Role of Ubiquitin-Specific Peptidase 47 in Cancers and Other Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Kailing Pan ◽  
Junhao Fu ◽  
Wenxia Xu
Keyword(s):  
Neuronal Development ◽  
Epithelial Mesenchymal Transition ◽  
Inflammatory Responses ◽  
Tumor Development ◽  
Post Translational Modifications ◽  
Mesenchymal Transition ◽  
Wide Range ◽  
Specific Protease ◽  
Range Of Functions ◽  
Targeted Inhibition

Deubiquitination is the reverse process of ubiquitination, which is catalyzed by deubiquitinase enzymes. More than 100 deubiquitinases have been identified. Ubiquitin-specific peptidase 47 (USP47), a member of the ubiquitin-specific protease family with high homology to USP7, is an active molecule with a wide range of functions and is closely associated with cancer and other diseases. However, no systematic summary exists regarding the functions of USP47. Here, we summarize the functions and expression regulation of USP47. USP47 is highly expressed in many tumors and is widely involved in tumor development, metastasis, drug resistance, epithelial-mesenchymal transition, and other processes. Targeted inhibition of USP47 can reverse malignant tumor behavior. USP47 also plays a role in inflammatory responses, myocardial infarction, and neuronal development. USP47 is involved in multiple levels of expression-regulating mechanisms, including transcriptional, post-transcriptional, and post-translational modifications. Development of targeted inhibitors against USP47 will provide a basis for studying the mechanisms of USP47 and developing therapeutic strategies for cancers and other diseases.

Cryptotanshinone Suppresses Liver Fibrosis by Attenuating Epithelial-Mesenchymal Transition through Targeting Hedgehog Pathway

2020 ◽  
Vol 20 ◽  
Author(s):  
Shurong Ren ◽  
Qizhen Yue ◽  
Qiubo Wang ◽  
Yanli Zhang ◽  
Bei Zhang
Keyword(s):  
Animal Model ◽  
Liver Fibrosis ◽  
Liver Diseases ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Chronic Liver ◽  
Luciferase Assay ◽  
Induced Expression ◽  
Mesenchymal Transition ◽  
Realtime Pcr

Background: Chronic liver damages from viral infection or alcohol abuse result in liver fibrosis, which is a key pathological event in many types of liver diseases. Discovering new anti-fibrosis agents may provide alternative solutions to manage chronic liver diseases. Methods: We first used CCl4 induced liver fibrosis animal model to evaluate the beneficial effects of Cryptotanshinone (CRY). We next explored target miRNAs regulated by CRY in hepatocytes using microarray. The target miRNA candidate was confirmed with realtime-PCR. We also elucidated the downstream target and pathway directly regulated by the miRNA using luciferase assay, western blotting and Epithelial–Mesenchymal Transition (EMT) markers quantification. Lastly, we confirmed CRY induced expression changes of the target genes in vivo. Results: CRY oral administration markedly alleviated the liver injury caused by CCl4. miRNAs expression profiling and realtime-PCR validation revealed miR-539-3p was directly induced by CRY around 4 folds. The induction of miR-539-3p suppressed SMO expression and antagonized Hedgehog (Hh) pathway. Independently CRY treatment suppressed SMO and inhibited EMT process in hepatocytes. The CRY induced expression changes of both miR-539-3p (~ 2 folds increase) and SMO (~ 60% decrease) in livers were validated in animal model. Conclusion: Our study supported CRY could inhibit liver fibrosis by targeting Hh pathway during EMT. CRY could be used as anti-fibrosis agent candidate for managing chronic liver damages.

scholarly journals Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells

Oncogene ◽  
2021 ◽  
Author(s):  
Kaisa-Mari Launonen ◽  
Ville Paakinaho ◽  
Gianluca Sigismondo ◽  
Marjo Malinen ◽  
Reijo Sironen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Protein A ◽  
Chorioallantoic Membrane ◽  
Chromatin Accessibility ◽  
Castration Resistant Prostate Cancer ◽  
Novel Therapy ◽  
Mesenchymal Transition

AbstractTreatment of prostate cancer confronts resistance to androgen receptor (AR)-targeted therapies. AR-associated coregulators and chromatin proteins hold a great potential for novel therapy targets. Here, we employed a powerful chromatin-directed proteomics approach termed ChIP-SICAP to uncover the composition of chromatin protein network, the chromatome, around endogenous AR in castration resistant prostate cancer (CRPC) cells. In addition to several expected AR coregulators, the chromatome contained many nuclear proteins not previously associated with the AR. In the context of androgen signaling in CRPC cells, we further investigated the role of a known AR-associated protein, a chromatin remodeler SMARCA4 and that of SIM2, a transcription factor without a previous association with AR. To understand their role in chromatin accessibility and AR target gene expression, we integrated data from ChIP-seq, RNA-seq, ATAC-seq and functional experiments. Despite the wide co-occurrence of SMARCA4 and AR on chromatin, depletion of SMARCA4 influenced chromatin accessibility and expression of a restricted set of AR target genes, especially those involved in cell morphogenetic changes in epithelial-mesenchymal transition. The depletion also inhibited the CRPC cell growth, validating SMARCA4’s functional role in CRPC cells. Although silencing of SIM2 reduced chromatin accessibility similarly, it affected the expression of a much larger group of androgen-regulated genes, including those involved in cellular responses to external stimuli and steroid hormone stimulus. The silencing also reduced proliferation of CRPC cells and tumor size in chick embryo chorioallantoic membrane assay, further emphasizing the importance of SIM2 in CRPC cells and pointing to the functional relevance of this potential prostate cancer biomarker in CRPC cells. Overall, the chromatome of AR identified in this work is an important resource for the field focusing on this important drug target.

scholarly journals The Role of microRNAs in Cholangiocarcinoma

2021 ◽  
Vol 22 (14) ◽  
pp. 7627
Author(s):  
Tingting Shi ◽  
Asahiro Morishita ◽  
Hideki Kobara ◽  
Tsutomu Masaki
Keyword(s):  
Cell Cycle Progression ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Survival Rates ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Mesenchymal Transition ◽  
Diagnosis And Prognosis ◽  
Related Risk

Cholangiocarcinoma (CCA), an aggressive malignancy, is typically diagnosed at an advanced stage. It is associated with dismal 5-year postoperative survival rates, generating an urgent need for prognostic and diagnostic biomarkers. MicroRNAs (miRNAs) are a class of non-coding RNAs that are associated with cancer regulation, including modulation of cell cycle progression, apoptosis, metastasis, angiogenesis, autophagy, therapy resistance, and epithelial–mesenchymal transition. Several miRNAs have been found to be dysregulated in CCA and are associated with CCA-related risk factors. Accumulating studies have indicated that the expression of altered miRNAs could act as oncogenic or suppressor miRNAs in the development and progression of CCA and contribute to clinical diagnosis and prognosis prediction as potential biomarkers. Furthermore, miRNAs and their target genes also contribute to targeted therapy development and aid in the determination of drug resistance mechanisms. This review aims to summarize the roles of miRNAs in the pathogenesis of CCA, their potential use as biomarkers of diagnosis and prognosis, and their utilization as novel therapeutic targets in CCA.

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