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Assessing the diagnostic utility of trna-derived fragments as biomarkers of head and neck cancer

TRANSLATIONAL ONCOLOGY 2024年 50卷 102135-102135页

作者： Uzelac, Matthew Ongkeko, Weg M. Univ Calif San Diego Dept Otolaryngol Head & Neck Surg La Jolla CA 92093 USA VA San Diego Healthcare Syst Res Serv San Diego CA 92161 USA Stanford Univ Sch Med Stanford CA 94305 USA

Roughly 54,000 individuals are diagnosed with head and neck cancers in the United States yearly. Transfer rna- derived fragments (tRF) are the products of enzymatic cleavage of precursor trnas, and have been proposed for use as biomarkers of head and neck cancer. In this study, we aim to further analyze the utility that tRFs might provide as biomarkers of head and neck cancer. tRF read counts were obtained for 453 tumor and 44 adjacent normal tissue samples and used to construct a gradient boosting diagnostic model. Although we identified 129 tRFs that were significantly dysregulated between these samples, the model achieved a sensitivity of only 69 % and a specificity of 59 %. tRFs are thought to induce the degradation of mrna transcripts containing a complementary "seed" region. Despite the above performances, we chose to explore this concept of translational regulation by analyzing these tRFs for inverse correlation to the expression of select oncogenes and tumor suppressor genes implicated in head and neck cancer. Among others, CysGCA 5 '-half '-half and LysCTT 3 '-tRF '-tRF were upregulated in the tumor samples, and corresponded to decreased expression of PIK3R1, AKT1, and CPEB3. These transcripts were further found to contain numerous significantly complementary sites at which tRFmediated mrna degradation might occur. Although these tRFs did appear to correlate to many of the oncogenic metrics analyzed, we believe that additional research is needed before they might be used to improve the diagnosis, treatment, and survival of patients with this disease.

关键词： trna-derived fragment non-coding rna Head and neck cancer

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The role of circrnas in resistance to doxorubicin

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CELL COMMUNICATION AND SIGNALING 2024年第1期22卷 1-20页

作者： Sanati, Mahla Ghafouri-Fard, Soudeh Shahid Beheshti Univ Med Sci Dept Med Genet Tehran Iran

Doxorubicin is an anthracyline recognized as an antitumor antibiotic agent. It is widely used in the chemotherapeutic regimens in different types of cancers. Resistance to doxorubicin is a major clinical obstacle and main cause of failure in cancer chemotherapy. Among different mechanisms involved in this process, the role of epigenetic factors has been highlighted. Circular rnas (circrnas) have a prominent role in this process. Here, we summarize the recent findings on the role of circrnas in doxorubicin resistance, particularly in breast cancer and osteosarcoma and underscore their clinical application as potential biomarkers and therapeutic targets in this field. Recognition of the underlying mechanism of circrnas involvement in doxorubicin resistance will expand our understanding of chemoresistance establishment and may provide a prospect to develop circrna-based predictive biomarkers of chemotherapy or therapeutic strategies for cancer patients.

关键词： Circrna non-coding rna Cancer Doxorubicin Circrna non-coding rna Cancer Doxorubicin

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Leaf Extract from European Olive (Olea europaea L.) Post-Transcriptionally Suppresses the Epithelial-Mesenchymal Transition and Sensitizes Gastric Cancer Cells to Chemotherapy

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BIOCHEMISTRY-MOSCOW 2024年第1期89卷 97-115页

作者： Tekin, Cagla Ercelik, Melis Dunaev, Pavel Galembikova, Aigul Tezcan, Gulcin Aksoy, Secil Ak Budak, Ferah Isik, Ozgen Ugras, Nesrin Boichuk, Sergei Tunca, Berrin Bursa Uludag Univ Fac Med Dept Med Biol Bursa Turkiye Kazan State Med Univ Dept Pathol Kazan Russia Bursa Uludag Univ Fac Dent Dept Fundamental Sci Bursa Turkiye Bursa Uludag Univ Inegol Vocat Sch Bursa Turkiye Bursa Uludag Univ Fac Med Expt Anim Breeding & Res Unit Bursa Turkiye Bursa Uludag Univ Fac Med Dept Immunol Bursa Turkiye Bursa Uludag Univ Fac Med Dept Gen Surg Bursa Turkiye Bursa Uludag Univ Fac Med Dept Pathol Bursa Turkiye Russian Med Acad Continuous Profess Educ Dept Radiotherapy & Radiol Moscow 125993 Russia Kazan Fed Univ Inst Fundamental Med & Biol Biomarker Res Lab Kazan Russia

The overall survival of patients with the advanced and recurrent gastric cancer (GC) remains unfavorable. In particular, this is due to cancer spreading and resistance to chemotherapy associated with the epithelial-mesenchymal transition (EMT) of tumor cells. EMT can be identified by the transcriptome profiling of GC for EMT markers. Indeed, analysis of the TCGA and GTEx databases (n = 408) and a cohort of GC patients (n = 43) revealed that expression of the CDH2 gene was significantly decreased in the tumors vs. non-tumor tissues and correlated with the overall survival of GC patients. Expression of the EMT-promoting transcription factors SNAIL and ZEB1 was significantly increased in GC. These data suggest that targeting the EMT might be an attractive therapeutic approach for patients with GC. Previously, we demonstrated a potent anti-cancer activity of the olive leaf extract (OLE). However, its effect on the EMT regulation in GC remained unknown. Here, we showed that OLE efficiently potentiated the inhibitory effect of the chemotherapeutic agents 5-fluorouracil (5-FU) and cisplatin (Cis) on the EMT and their pro-apoptotic activity, as was demonstrated by changes in the expression of the EMT markers (E- and N-cadherins, vimentin, claudin-1) in GC cells treated with the aforementioned chemotherapeutic agents in the presence of OLE. Thus, culturing GC cells with 5-FU + OLE or Cis + OLE attenuated the invasive properties of cancer cells. Importantly, upregulation of expression of the apoptotic markers (PARP cleaved form) and increase in the number of cells undergoing apoptosis (annexin V-positive) were observed for GC cells treated with a combination of OLE and 5-FU or Cis. Collectively, our data illustrate that OLE efficiently interferes with the EMT in GC cells and potentiates the pro-apoptotic activity of certain chemotherapeutic agents used for GC therapy.

关键词： gastric cancer Olea europaea leaf extract epithelial-mesenchymal transition apoptosis chemotherapeutic agents cadherin 2 SOX2 non-coding rna miR-23b-3p anti-cancer effect

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Epigenetic regulation of bone remodeling and bone metastasis

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SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY 2024年第PartC期154卷 275-285页

作者： Sharma, Gunjan Sultana, Ashrafi Abdullah, K. M. Pothuraju, Ramesh Nasser, Mohd Wasim Batra, Surinder Kumar Siddiqui, Jawed Akhtar Univ Nebraska Med Ctr Dept Biochem Mol Biol Omaha NE 68198 USA Univ Nebraska Med Ctr Fred & Pamela Buffett Canc Ctr Omaha NE 68198 USA Univ Nebraska Med Ctr Eppley Inst Res Canc & Allied Dis Omaha NE 68198 USA Univ Nebraska Med Ctr Fred & Pamela Buffett Canc Ctr Dept Biochem & Mol Biol Omaha NE 68198 USA

Bone remodeling is a continuous and dynamic process of bone formation and resorption to maintain its integrity and homeostasis. Bone marrow is a source of various cell lineages, including osteoblasts and osteoclasts, which are involved in bone formation and resorption, respectively, to maintain bone homeostasis. Epigenetics is one of the elementary regulations governing the physiology of bone remodeling. Epigenetic modifications, mainly DNA methylation, histone modifications, and non-coding rnas, regulate stable transcriptional programs without causing specific heritable alterations. DNA methylation in CpG-rich promoters of the gene is primarily correlated with gene silencing, and histone modifications are associated with transcriptional activation/inactivation. However, non-coding rnas regulate the metastatic potential of cancer cells to metastasize at secondary sites. Deregulated or altered epigenetic modifications are often seen in many cancers and interwound with bonespecific tropism and cancer metastasis. Histone acetyltransferases, histone deacetylase, and DNA methyltransferases are promising targets in epigenetically altered cancer. High throughput epigenome mapping and targeting specific epigenetics modifiers will be helpful in the development of personalized epi-drugs for advanced and bone metastasis cancer patients. This review aims to discuss and gather more knowledge about different epigenetic modifications in bone remodeling and metastasis. Further, it provides new approaches for targeting epigenetic changes and therapy research.

关键词： Bone remodeling Epigenetic modification DNA methylation Acetylation Histone modifications Microrna non-coding rna Long non-coding rna Circular rna And Bone metastasis

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Circular rna circZFPM2 regulates cardiomyocyte hypertrophy and survival

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BASIC RESEARCH IN CARDIOLOGY 2024年第4期119卷 613-632页

作者： Neufeldt, Dimyana Schmidt, Arne Mohr, Elisa Lu, Dongchao Chatterjee, Shambhabi Fuchs, Maximilian Xiao, Ke Pan, Wen Cushman, Sarah Jahn, Christopher Juchem, Malte Hunkler, Hannah Jill Cipriano, Giuseppe Juergens, Bjarne Schmidt, Kevin Gross, Sonja Jung, Mira Hoepfner, Jeannine Weber, Natalie Foo, Roger Pich, Andreas Zweigerdt, Robert Kraft, Theresia Thum, Thomas Baer, Christian Hannover Med Sch Inst Mol & Translat Therapeut Strategies Hannover Germany Hannover Med Sch Ctr Translat Regenerat Med Hannover Germany Fraunhofer Inst Toxicol & Expt Med ITEM Hannover Germany Inst Mol & Cell Biol AStar Singapore Singapore Inst Toxicol Hannover Med Sch Hannover Germany Inst Toxicol Core Facil Prote Hannover Germany Hannover Med Sch Dept Cardiothorac Transplantat & Vasc Surg Leibniz Res Labs Biotechnol & Artificial Organs LE Hannover Germany Hannover Med Sch Inst Mol & Cell Physiol Hannover Germany

Hypertrophic cardiomyopathy (HCM) constitutes the most common genetic cardiac disorder. However, current pharmacotherapeutics are mainly symptomatic and only partially address underlying molecular mechanisms. Circular rnas (circrnas) are a recently discovered class of non-coding rnas and emerged as specific and powerful regulators of cellular functions. By performing global circrna-specific next generation sequencing in cardiac tissue of patients with hypertrophic cardiomyopathy compared to healthy donors, we identified circZFPM2 (hsa_circ_0003380). CircZFPM2, which derives from the ZFPM2 gene locus, is a highly conserved regulatory circrna that is strongly induced in HCM tissue. In vitro loss-of-function experiments were performed in neonatal rat cardiomyocytes, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and HCM-patient-derived hiPSC-CMs. A knockdown of circZFPM2 was found to induce cardiomyocyte hypertrophy and compromise mitochondrial respiration, leading to an increased production of reactive oxygen species and apoptosis. In contrast, delivery of recombinant circZFPM2, packaged in lipid-nanoparticles or using AAV-based overexpression, rescued cardiomyocyte hypertrophic gene expression and promoted cell survival. Additionally, HCM-derived cardiac organoids exhibited improved contractility upon CM-specific overexpression of circZFPM2. Multi-Omics analysis further promoted our hypothesis, showing beneficial effects of circZFPM2 on cardiac contractility and mitochondrial function. Collectively, our data highlight that circZFPM2 serves as a promising target for the treatment of cardiac hypertrophy including HCM.

关键词： Cardiac hypertrophy Hypertrophic cardiomyopathy non-coding rna Circular rna Human induced pluripotent stem cell-derived cardiomyocytes Heart organoids

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Circrna_SLC8A1 alleviates hypertrophic scar progression by mediating the Nrf2-ARE pathway

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MOLECULAR BIOLOGY REPORTS 2024年第1期51卷 1067页

作者： Jin, Yichao He, Yongjing Wu, Yifei Wang, Xiaochuan Lyu, Lechun Zhang, Ke Ao, Chunping Xu, Liangheng First Peoples Hosp Yunnan Prov Dept Dermatol Kunming Yunnan Peoples R China Kunming Univ Sci & Technol Affiliated Hosp Dept Dermatol Kunming Yunnan Peoples R China Kunming Med Univ Affiliated Hosp 2 Dept Plast Surg Kunming Yunnan Peoples R China Kunming Med Univ Technol Transfer Ctr Kunming Yunnan Peoples R China First Peoples Hosp Yunnan Prov Dept Urinary Surg Kunming Yunnan Peoples R China Kunming Univ Sci & Technol Dept Ultrasound Affiliated Hosp Kunming Yunnan Peoples R China

BackgroundHypertrophic scar (HS) is associated with cosmetic defects, mobility, and functional impairments, pruritus, and pain. Previous circrna microarray analysis identified reduced expression of circrna_SLC8A1 in HS tissues. Therefore, this study aims to investigate the role of circrna_SLC8A1 in modulating the abnormal behavior of HS-derived fibroblasts (HSFs) in ***-qPCR and FISH assays were used to assess the differential expression and localization of circrna_SLC8A1 in normal and HS tissues. Following modulation of circrna_SLC8A1 expression, CCK-8, flow cytometry, Transwell, and wound healing assays were employed to evaluate the effects of circrna_SLC8A1 on the biological behaviors of HSFs. The Starbase database, dual-luciferase reporter assays, and Ago2-RIP assays were utilized to predict and validate the interaction between circrna_SLC8A1 and downstream ***_SLC8A1 was found to be downregulated in HS tissues and was primarily localized in the cytoplasm. Overexpression of circrna_SLC8A1 reduced cell viability, cell invasion, wound healing, and the expression of Vimentin, N-cadherin, Col I, and Col III, while enhancing apoptosis and E-cadherin expression in HSFs. Circrna_SLC8A1 activates the Nrf2-ARE pathway by competitively binding to mirna-27a-3p. mirna-27a-3p and Nrf2 exhibited high and low expression, respectively in HS tissues, with an inverse correlation between their levels. Overexpression of mirna-27a-3p counteracted the effects of circrna_SLC8A1 in HSF proliferation, apoptosis, migration, EMT, collagen deposition, and Nrf2-ARE pathway ***_SLC8A1 inhibits the proliferation, migration, EMT, and collagen deposition of HSF through competitive binding with mirna-27a-3p, thereby activating the Nrf2-ARE pathway. The circrna_SLC8A1/mirna-27a-3p/Nrf2-ARE axis may offer a promising molecular target for HS therapy.

关键词： Hypertrophic scar Epithelial-mesenchymal transition Collagen deposition non-coding rna Nrf2-ARE pathway

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Epigenetics in diabetic cardiomyopathy

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CLINICAL EPIGENETICS 2024年第1期16卷 52页

作者： Ma, Xiaozhu Mei, Shuai Wuyun, Qidamugai Zhou, Li Sun, Dating Yan, Jiangtao Huazhong Univ Sci & Technol Tongji Med Coll Tongji Hosp Div CardiolDept Internal Med Wuhan Peoples R China Hubei Key Lab Genet & Mol Mech Cardiol Disorders Wuhan Peoples R China Wuhan Hosp Tradit Chinese & Western Med Wuhan Hosp 1 Dept Cardiol Wuhan Peoples R China Huazhong Univ Sci & Technol Tongji Med Coll Tongji Hosp Genet Diag Ctr Wuhan Peoples R China

Diabetic cardiomyopathy (DCM) is a critical complication that poses a significant threat to the health of patients with diabetes. The intricate pathological mechanisms of DCM cause diastolic dysfunction, followed by impaired systolic function in the late stages. Accumulating researches have revealed the association between DCM and various epigenetic regulatory mechanisms, including DNA methylation, histone modifications, non-coding rnas, and other epigenetic molecules. Recently, a profound understanding of epigenetics in the pathophysiology of DCM has been broadened owing to advanced high-throughput technologies, which assist in developing potential therapeutic strategies. In this review, we briefly introduce the epigenetics regulation and update the relevant progress in DCM. We propose the role of epigenetic factors and non-coding rnas (ncrnas) as potential biomarkers and drugs in DCM diagnosis and treatment, providing a new perspective and understanding of epigenomics in DCM.

关键词： Diabetic cardiomyopathy Epigenetic regulation DNA methylation Histone modification non-coding rna

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Epigenetic-modifying agents: The potential game changers in the treatment of hematologic malignancies

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CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY 2024年 204卷 104498-104498页

作者： Hojjatipour, Tahereh Ajeli, Mina Maali, Amirhosein Azad, Mehdi Univ Nottingham Sch Med Canc Immunol Grp Biodiscovery Inst Nottingham England Guilan Univ Med Sci Dept Med Lab Sci Guilan Iran Pasteur Inst Iran Dept Immunol Tehran Iran Qazvin Univ Med Sci Fac Allied Med Dept Med Biotechnol Qazvin Iran Qazvin Univ Med Sci Sch Paramed Dept Med Lab Sci Qazvin Iran

Hematologic malignancies are lethal diseases arising from accumulated leukemic cells with substantial genetic or epigenetic defects in their natural development. Epigenetic modifications, including DNA methylation and histone modifications, are critical in hematologic malignancy formation, propagation, and treatment response. Both mutations and aberrant recruitment of epigenetic modifiers are reported in different hematologic malignancies, which regarding the reversible nature of epigenetic regulations, make them a potential target for cancer treatment. Here, we have first outlined a comprehensive overview of current knowledge related to epigenetic regulation's impact on the development and prognosis of hematologic malignancies. Furthermore, we have presented an updated overview regarding the current status of epigenetic-based drugs in hematologic malignancies treatment. And finally, discuss current challenges and ongoing clinical trials based on the manipulation of epigenetic modifies in hematologic malignancies.

关键词： Epigenetic Hematologic malignancies Methylation Histone modifications non-coding rna Cancer treatment

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The Rejuvenation and Functional Restoration of Aged Adipose Stem Cells by DUXAP10 Knockdown via the Regulation of the miR-214-3p/RASSF5 Axis

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STEM CELLS TRANSLATIONAL MEDICINE 2024年第5期13卷 462-476页

作者： Ren, Sen Li, Chengcheng Xiong, Hewei Wu, Qian Wu, Xiaohui Xiong, Zhongwei Dong, Lixing Shu, Bing Wei, Wei Ma, Chao Li, Xiang Chen, Jincao Wuhan Univ Zhongnan Hosp Dept Neurosurg Wuhan 430071 Peoples R China Huazhong Univ Sci & Technol Union Hosp Tongji Med Coll Dept Hand Surg Wuhan Peoples R China Huazhong Univ Sci & Technol Tongji Med Coll Union Hosp Dept Emergency Surg Wuhan Peoples R China Wuhan Univ Brain Res Ctr Zhongnan Hosp Wuhan Peoples R China Wuhan Univ Med Res Inst Wuhan Peoples R China

Adipose stem cell (ASC)-based therapies provide an encouraging option for tissue repair and regeneration. However, the function of these cells declines with aging, which limits their clinical transformation. Recent studies have outlined the involvement of long non-coding rnas in stem cell aging. Here, we reanalyzed our published rna sequencing (rna-seq) data profiling differences between ASCs from young and old donors and identified a lncrna named double homeobox A pseudogene 10 (DUXAP10) as significantly accumulated in aged ASCs. Knocking down DUXAP10 promoted stem cell proliferation and migration and halted cell senescence and the secretion of proinflammatory cytokines. In addition, DUXAP10 was located in the cytoplasm and functioned as a decoy for miR-214-3p. miR-214-3p was downregulated in aged ASCs, and its overexpression rejuvenated aged ASCs and reversed the harm caused by DUXAP10. Furthermore, Ras Association Domain Family Member 5 (RASSF5) was the target of miR-214-3p and was upregulated in aged ASCs. Overexpressing DUXAP10 and inhibiting miR-214-3p both enhanced RASSF5 content in ASCs, while DUXAP10 knockdown promoted the therapeutic ability of aged ASCs for skin wound healing. Overall, this study offers new insights into the mechanism of age-related ASC dysfunction and names DUXAP10 and miR-214-3p as potential targets for energizing aged stem cells. Graphical Abstract

关键词： adipose stem cell aging non-coding rna DUXAP10 miR-214-3p RASSF5

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non-coding 886 (nc886/vtrna2-1), the epigenetic odd duck - implications for future studies

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EPIGENETICS 2024年第1期19卷

作者： Raitoharju, Emma Rajic, Sonja Marttila, Saara Tampere Univ Fac Med & Hlth Technol Mol Epidemiol Arvo Ylpon Katu 34 Tampere 33520 Finland Tampere Univ Fac Med & Hlth Technol Finnish Cardiovasc Res Ctr Tampere Tampere Finland Tampere Univ Hosp Tays Res Serv Wellbeing Serv Cty Pirkanmaa Tampere Finland Tampere Univ Gerontol Res Ctr Tampere Finland

non-coding 886 (nc886, vtrna2-1) is the only human polymorphically imprinted gene, in which the methylation status is not determined by genetics. Existing literature regarding the establishment, stability and consequences of the methylation pattern, as well as the nature and function of the nc886 rnas transcribed from the locus, are contradictory. For example, the methylation status of the locus has been reported to be stable through life and across somatic tissues, but also susceptible to environmental effects. The nature of the produced nc886 rna(s) has been redefined multiple times, and in carcinogenesis, these rnas have been reported to have conflicting roles. In addition, due to the bimodal methylation pattern of the nc886 locus, traditional genome-wide methylation analyses can lead to false-positive results, especially in smaller datasets. Herein, we aim to summarize the existing literature regarding nc886, discuss how the characteristics of nc886 give rise to contradictory results, as well as to reinterpret, reanalyse and, where possible, replicate the results presented in the current literature. We also introduce novel findings on how the distribution of the nc886 methylation pattern is associated with the geographical origins of the population and describe the methylation changes in a large variety of human tumours. Through the example of this one peculiar genetic locus and rna, we aim to highlight issues in the analysis of DNA methylation and non-coding rnas in general and offer our suggestions for what should be taken into consideration in future analyses.

关键词： nc886 vtrna2-1 epigenetics DNA methylation non-coding rna

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