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Breast cancer epigenetic targets for precision medicine
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
In addition, in the ER+ breast cancers, the RUNX3 hypermethylation was frequently observed and a higher RUNX3 mRNA expression was associated with better relapse-free survival (Lu et al., 2017). Thus, RUNX3 methylation could be a therapeutic target for the development of personalized therapy.
Malignant Tumours of the Salivary Glands
Published in John C Watkinson, Raymond W Clarke, Terry M Jones, Vinidh Paleri, Nicholas White, Tim Woolford, Head & Neck Surgery Plastic Surgery, 2018
Vincent Vander Poorten, Patrick J. Bradley
The above-mentioned growth factor-receptor interaction activates cell cycle oncogenes. These include sex-determining region Y-box 4 (SOX-4), nuclear factor κB (NFκB), human rat sarcoma viral oncogene homolog (H-RAS), phosphatidylinositol 3 phosphate kinase/serine-threonine protein kinase Akt (PI3K/AKT), sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (Src), signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin (mTOR, activated by AKT regulates protein synthesis depending on nutrient availability), peroxisome proliferator-activated receptor gamma (PPARgamma), and cyclin D1. In a large microarray analysis of AdCC, Frierson et al. found that SOX-4 was the most significantly overexpressed cell cycle oncogene.156 Furthermore, increased apoptosis following SOX-4 knockdown suggests that this oncogene exerts its activity via down-regulation of inhibitors of the NFκB pathway (inhibitor protein (I-κB)-α) and by up-regulation of apoptosis inhibitors such as survivin. Mutations of H-RAS are observed in carcinoma ex-pleomorphic adenoma, in adenocarcinoma and in almost half of MECs, where the frequency of H-RAS mutations parallels tumour grade. Cyclin D1 seems frequently overexpressed in AdCC and MEC and correlates with prognosis. In MEC, high-cyclin D1 expression follows inactivation of secreted frizzled-related proteins (SFRPs) by hypermethylation. Nuclear pSTAT3 expression seems to play a role as tumour suppressor in the absence of EGFR, HER-2, and survivin in SGC. RUNX3, a tumour suppressor gene that, when active, facilitates TGF-beta to play its apoptotic role, appears silenced by hypermethylation in AdCC. RB1-inducible coiled-coil 1 (RB1CC1) is a positive regulator for the retinoblastoma tumour suppressor (RB1) pathway, and its expression in SGC implies better prognosis, analogous to observations in breast cancer. Efforts are underway at targeting the PI3K/AKT pathway by blocking mTOR with temsirolimus.
Molecular Genetics of Cleidocranial Dysplasia
Published in Fetal and Pediatric Pathology, 2021
Jamshid Motaei, Arash Salmaninejad, Ebrahim Jamali, Imaneh Khorsand, Mohammad Ahmadvand, Sasan Shabani, Farshid Karimi, Mohammad Sadegh Nazari, Golsa Ketabchi, Fatemeh Naqipour
Thirty percent of patients with acute myeloid leukemia (AML) and ten percent of patients with myelodysplasia (MDS) have mutations in the RUNX1 gene [12]. RUNX1 plays an important role in hematopoietic cells. Hereditary mutation in RUNX1 causes familial platelet disorder with predisposition to myeloid malignancy (FPD/AML) with autosomal dominate inheritance pattern [13]. RUNX2 plays an important role in the development of the skeletal system and the morphogenesis of other organs, such as thyroid and breast. The role of RUNX2 is increasingly recognized in various cancers, including thyroid, prostate, lung and breast cancer. Many studies have shown that the deregulation of RUNX2 is associated with the progression and metastasis of various tumors [14–17]. RUNX3 is a tumor suppressor gene that plays a role in various biological processes, including development of the cranial and dorsal root ganglia, gastrointestinal tract and T-cell differentiation. Mutations in RUNX3 have been reported in various diseases including colon and gastric cancers, glioma, melanoma, prostate cancer, renal cell carcinoma and neural disorders [18].
LncRNA PART1/miR-185-5p/RUNX3 feedback loop modulates osteogenic differentiation of bone marrow mesenchymal stem cells
Published in Autoimmunity, 2021
Junjie Zhang, Nanwei Xu, Changlin Yu, Kaisong Miao, Qiugen Wang
Previous research suggested that abnormal osteogenic differentiation of BMSCs is the main cause of OP [21,22]. Thus, regulation of BMSCs osteogenic differentiation is a vital focus in OP pathogenesis research. Emerging evidence unravelled that lncRNAs served essential roles in various diseases, including OP [23,24]. Moreover, previous researches exhibited that PART1 was involved in the development of bone disease. For example, PART1 acted as an oncogene in osteosarcoma by regulating miR-20b-5p to enhance BAMBI [25]. Upregulated PART1 promoted the viability and decreased cell apoptosis of chondrocytes through miR-590-3p/TGFBR2 in osteoarthritis [26]. Nevertheless, the molecular mechanism of PART1 in OP is unclear. In this work, we found that PART1 was overexpressed during osteogenic differentiation of hBMSCs, and knockdown of PART1 impaired hBMSC osteogenic differentiation. In addition, the upstream regulatory mechanism of PART1 was further explored. Runt-related transcription factor 3 (RUNX3) is a member of the RUNX family, which has been reported to be an inducer of osteoblast differentiation [27,28]. In addition, RUNX3 was identified as a transcription activator of various genes, including lncRNAs [29,30]. Herein, we demonstrated that RUNX3 served as a transcriptional activator of PART1.
Delayed neutrophil apoptosis in granulomatosis with polyangiitis: dysregulation of neutrophil gene signature and circulating apoptosis-related proteins
Published in Scandinavian Journal of Rheumatology, 2020
M Surmiak, M Hubalewska-Mazgaj, K Wawrzycka-Adamczyk, J Musiał, M Sanak
RUNX3 transcription factor has been proposed as a master controller for the expression of PR3 and MPO in GPA (33). However, this protein can also participate in apoptosis. In cancerous cells, RUNX3 can control the expression of anti-apoptotic CFLAR and pro-apoptotic CASP3 and BAX (34–36). Our results seem consistent with this view. In neutrophils from GPA patients, expression of CASP3 and BAX was down-regulated, whereas expression of CFLAR was up-regulated. There was a positive correlation between RUNX3 mRNA and CASP3 or BAX, and negative correlation with CLFAR. RUNX3 mRNA correlated positively with the percentage of circulating apoptotic neutrophils. Moreover, RUNX3 can also regulate the function of other transcription factors related to apoptosis, e.g. p53. Zhai et al showed that RUNX3 can act as a co-activator of this transcription factor and has an impact on p53 phosphorylation (36). Since p53 responsive elements were identified in apoptosis-related genes such as PMAIP1 or BAX (37–39), some activity downstream of p53 can occur. In our study, decreased expression of PMAIP1 or BAX was accompanied by decreased TP53 mRNA transcripts in neutrophils from GPA patients.