DNA Replication Inhibitor Geminin and Retinoic Acid Signaling Participate in Complex Interactions Associated With Pluripotency

Tsaniras, Spyridon Champeris; Petropoulos, Michalis; Παναγόπουλος, Ανδρέας; Anagnostopoulos, Athanasios; Villiou, Maria; Vlachakis, Dimitriοs; Bravou, Vasiliki; Stathopoulos, Georgios T.; Taraviras, Stavros

doi:10.21873/cgp.20162

Cited by 11 publications

(6 citation statements)

References 88 publications

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“…Geminin, a DNA replication inhibitor, is activated during cell cycle-progression by the anaphase-promotion complex (APC) leading to initiation of sister chromatid separation [77]. The specific role of geminin is to limit DNA replication and trigger sister chromatid separation and, therefore, it is considered to qualify exceptionally well as a cell cyclespecific proliferation marker [78][79][80]. In previous literature, loss of geminin expression has been observed to predict poor survival in breast cancer [81][82][83] and aggressive course of disease in the subgroup of TNBCs [84][85][86].…”

Section: Discussionmentioning

confidence: 99%

Varying outcomes of triple-negative breast cancer in different age groups–prognostic value of clinical features and proliferation

Vihervuori

Korpinen

Autere

et al. 2022

Breast Cancer Res Treat

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Purpose Triple-negative breast cancer (TNBC) is an aggressive disease lacking specific biomarkers to guide treatment decisions. We evaluated the combined prognostic impact of clinical features and novel biomarkers of cell cycle-progression in age-dependent subgroups of TNBC patients. Methods One hundred forty seven TNBC patients with complete clinical data and up to 18 year follow-up were collected from Turku University Hospital, Finland. Eight biomarkers for cell division were immunohistochemically detected to evaluate their clinical applicability in relation to patient and tumor characteristics. Results Age at diagnosis was the decisive factor predicting disease-specific mortality in TNBC (p = 0.002). The established prognostic features, nodal status and Ki-67, predicted survival only when combined with age. The outcome and prognostic features differed significantly between age groups, middle-aged patients showing the most favorable outcome. Among young patients, only lack of basal differentiation predicted disease outcome, indicating 4.5-fold mortality risk (p = 0.03). Among patients aged > 57, the established prognostic features predicted disease outcome with up to 3.0-fold mortality risk for tumor size ≥ 2 cm (p = 0.001). Concerning cell proliferation, Ki-67 alone was a significant prognosticator among patients aged > 57 years (p = 0.009). Among the studied cell cycle-specific biomarkers, only geminin predicted disease outcome, indicating up to 6.2-fold increased risk of mortality for tumor size < 2 cm (p = 0.03). Conclusion Traditional clinical features do not provide optimal prognostic characterization for all TNBC patients. Young age should be considered as an additional adverse prognostic feature in therapeutic considerations. Increased proliferation, as evaluated using Ki-67 or geminin immunohistochemistry, showed potential in detecting survival differences in subgroups of TNBC.

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Section: Discussionmentioning

confidence: 99%

Varying outcomes of triple-negative breast cancer in different age groups–prognostic value of clinical features and proliferation

Vihervuori

Korpinen

Autere

et al. 2022

Breast Cancer Res Treat

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“…Nevertheless, the function of multiple miRNAs can be ambiguous, and some transcripts are described as both oncomirs and tumour suppressors, such as mir155 (36,37). Most identified miRNAs mediate in various pathophysiological conditions, such as cancer (38), chronic inflammatory diseases (39,40), osteoporosis and diabetes (41), through interfering in different molecular and metabolic pathways: targeting tumour-suppressor genes and activating oncogenic transcription factors (42), affecting cell cycle arrest, pluripotency (43), glucose metabolism (44) and angiogenesis (45). Some miRNAs have already been associated with CRC risk, patient prognosis or treatment outcomes (11).…”

Section: Discussionmentioning

confidence: 99%

Machine-learning-based Analysis Identifies miRNA Expression Profile for Diagnosis and Prediction of Colorectal Cancer: A Preliminary Study

Pawełka

Łaczmańska

Karpiński

et al. 2022

Cancer Genomics Proteomics

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Background: The stage of colorectal cancer (CRC) at the day of diagnosis has the greatest influence on survival rate. Thus, for CRC, which is mainly identified as advanced disease, non-invasive, molecular blood or stool tests could boost the diagnosis and lower mortality. Evaluation of miRNA expression levels in serum of patients diagnosed with CRC is a potential tool in early screening. Screening can be supported by machine learning (ML) as a tool for developing a cancer risk predictive model based on genetic data. Materials and Methods: miRNA was isolated from the serum of 8 patients diagnosed with CRC and 10 patients from a control group matched for age and sex. The expression of 179 miRNAs was determined using a serum/plasma panel (Exiqon). Determinations were conducted using real-time PCR technique on an Applied Biosystems QuantStudio3 device in 96-well plates. A predictive model was developed through the Azure Machine Learning platform. Results: A wide panel of 29 up-regulated miRNAs in CRC were identified and divided into two subgroups: 1) miRNAs with significantly higher serum level in cancer patients vs. controls (24 miRNAs) and 2) miRNAs detected only in cancer patients and not in controls ( 5 miRNAs). Re-analysis of published miRNA profiles of CRC tumours or CRC exosomes revealed that only 2 out of 29 miRNAs were up-regulated in all datasets including ours (miR-34a and miR-25-3p). Conclusion: Our research suggests the potential role of overexpressed miRNAs as diagnostic or prognostic biomarkers among CRC patients. Such clustering of miRNAs may be a potential direction for discovering new diagnostic panels of cancer (including CRC), especially using ML. The low correspondence between deregulation of miRNAs in serum and tumour tissue revealed in our study confirms previously published reports.Colorectal cancer (CRC) is one of the most common cancers and the third leading cause of cancer-related deaths, especially in developed countries (1). Morbidity from CRC is strongly related to certain environmental factors, such as low-fibre diet, addictions (alcohol consumption and smoking) and lack of physical activity (2, 3). Because of the high frequency and impact of CRC on general public health, the studies on its genetic background include searching early genetic markers of this cancer at the chromosomal, molecular, and epigenetic levels (4, 5). Although some noninvasive techniques for CRC screening exist, colonoscopy still remains the gold standard (6). As some patients avoid or refuse this procedure, establishing a new genetic screening test from blood would be greatly beneficial for CRC prevention and early diagnosis.The stage of CRC at the day of diagnosis plays the largest role in survival rates. Notably, when CRC is diagnosed at a localized stage, the 5-year survival rate ranges between 89% 503 # These Authors contributed equally to this study.

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“…Multiple functions of miRs regulating the cell cycle have been documented. In addition to targeting components of the cell-cycle (129), they can regulate DNA damage response (130), licensing of DNA replication (131), modulation of activity of DNA replication inhibitor geminin, retinoic acid signaling and pluripotency (132).…”

Section: Micro-rnas Targeting Cell Cycle-related Proteinsmentioning

confidence: 99%

Clear Cell Renal Carcinoma: MicroRNAs With Efficacy in PreclinicalIn VivoModels

Weidle

Nopora

2021

Cancer Genomics Proteomics

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In order to identify new targets and treatment modalities for clear cell renal carcinoma, we surveyed the literature with respect to microRNAs involved in this disease. In this review, we have focused on up-and down-regulated miRs which mediate efficacy in preclinical clear-cell renal carcinoma-related in vivo models. We have identified 10 upregulated and 33 down-regulated micro-RNAs according to this criterion. As proof-of-concept, micro-RNAs interfering with VEGF (miR-205p) and mTOR (mir-99a) pathways, which are modulated by approved drugs for this disease, have been identified. miRs targeting hypoxia induced factor-2α (HIF-2α) (miR-145), E3 ubiquitinylases speckle-type POZ protein (SPOP) (miR 520/372/373) and casitas B-lineage lymphoma (CBL) (miR-200a-3p), interfere with druggable targets. Further identified miRs interfere with cell-cycle dependent kinases, such as CDK2 CDK4, 9 (206c). Transmembrane receptor Ral interacting protein of 76 kD (RLIP76), targeted by mir-137, has emerged as another important target for ccRCC. Additional miRs and their targets merrying further preclinical validation are discussed.

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DNA Replication Inhibitor Geminin and Retinoic Acid Signaling Participate in Complex Interactions Associated With Pluripotency

Cited by 11 publications

References 88 publications

Varying outcomes of triple-negative breast cancer in different age groups–prognostic value of clinical features and proliferation

Varying outcomes of triple-negative breast cancer in different age groups–prognostic value of clinical features and proliferation

Machine-learning-based Analysis Identifies miRNA Expression Profile for Diagnosis and Prediction of Colorectal Cancer: A Preliminary Study

Clear Cell Renal Carcinoma: MicroRNAs With Efficacy in PreclinicalIn VivoModels

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