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CDK7 inhibitor THZ1 suppresses TNBC growth via RARαS77-DHRS3 signaling. a Western blotting analysis of RARα (p-Ser77) and RARα protein expression levels after treatment of THZ1 for 48 h. b TNBC cell viability was assessed after THZ1 treatment by MTT analysis and IC 50 values were calculated. c qRT-PCR and western blotting analysis of DHRS3 levels after THZ1 treatment
Source publication
Background:
Retinoids are promising agents in the treatment of different types of neoplasia including estrogen receptor-positive breast cancers, whereas refractoriness/low sensitivity is observed in triple-negative breast cancer (TNBC) subtype. However, the reason for these diverse retinoid-sensitivity remains elusive.
Methods:
Determinants of r...
Contexts in source publication
Context 1
... DHRS3 or DHRS3-Y188H mutant, in the presence or absence of different RARs agonists. * p < 0.05, ** p < 0.01, *** p < 0.001 treatment strategy to reduce phosphorylation of RARαS77 in TNBC cells. As expected, a highly specific covalent CDK7 inhibitor THZ1 [41] markedly suppressed RARαS77 phosphorylation as well as TNBC cell growth in vitro (Fig. 8a-b). This anti-tumor action of THZ1 may be attributed to the down-regulation of DHRS3 (Fig. 8c). Thus, targeting the phosphokinase of RARαS77 may be a feasible approach to treat RAresistant ...
Context 2
... p < 0.05, ** p < 0.01, *** p < 0.001 treatment strategy to reduce phosphorylation of RARαS77 in TNBC cells. As expected, a highly specific covalent CDK7 inhibitor THZ1 [41] markedly suppressed RARαS77 phosphorylation as well as TNBC cell growth in vitro (Fig. 8a-b). This anti-tumor action of THZ1 may be attributed to the down-regulation of DHRS3 (Fig. 8c). Thus, targeting the phosphokinase of RARαS77 may be a feasible approach to treat RAresistant ...
Citations
... Studies have shown that DHRS3 is poorly expressed in gastric cancer tissues, and DHRS3 can promote the progression of gastric cancer in vitro. In addition, DHRS3 has also been reported to promote the progression of breast cancer [26,27]. ...
Background
Papillary thyroid cancer (PTC) is the most common thyroid tumor (TC). However, there is still a lack of effective indicators for PTC detection and prognosis. We intended to find a novel tumor marker for the progression of PTC.
Methods
The expression of circRNAs was measured by quantitative real-time polymerase chain reaction (qRT-PCR). SiRNA transfection was used to knockdown the expression of hsa_circ_0010023 in K1 cells. Cell proliferation was evaluated using cell counting and CCK8. Cell apoptosis was analyzed using flow cytometry. Hsa_circ_0010023 downstream pathways were predicted with bio-informatics analysis. The miR-1250-5p and MAPK1 were measured by qRT-PCR. The interaction between miR-1250-5p and hsa_circ_0010023 was vertified by dual-luciferase reporter assay.
Results
Among the four circRNAs screened, only hsa_circ_0010023 and hsa_circ_0128482 were highly expressed in PTC (P < 0.05). The expression of hsa_circ_0010023 was significantly correlated with lymph node metastasis and extrathyroid infiltration (P < 0.05). Compared with the control group, the cell proliferation of the si-circ-0010023 group was significantly inhibited (P < 0.05). Knockdown of hsa_circ_0010023 promotes apoptosis of K1 cells (P < 0.001). The expression of hsa_circ_0010023 was negatively correlated with miR-1250-5p and positively correlated with MAPK1. MiR-1250-5p overexpression significantly reduced the luciferase activity of wild type plasmid (hsa_circ_0010023 WT), but not that of mutant type plasmid (hsa_circ_0010023 MUT).
Conclusion
The expression level of hsa_circ_0010023 was positive related to the progression of PTC, and hsa_circ_0010023 may promote PTC through sponging miR-1250-5p. Hsa_circ_0010023 may be a potential bio-marker for the diagnosis of PTC.
... ER-negative breast cancer cells express lower levels of retinoic acid receptors (RARs)-β compared to their ER-positive counterparts [28]. This suggests a nuanced relationship between β-carotene, RA, and breast cancer prognosis, with differential effects based on one's hormone receptor status. ...
Breast cancer is one of the most common cancers worldwide, at the same time being one of the most prevalent causes of women's death. Many factors such as alcohol, weight fluctuations, or hormonal replacement therapy can potentially contribute to breast cancer development and progression. Another important factor in breast cancer onset includes micronutrient status. In this narrative review, we analyzed 23 micronutrients and their possible influence on breast cancer onset and progression. Further, the aim of this study was to investigate the impact of micronutrient status on the prevention of breast cancer and its possible influence on various therapeutic pathways. We researched meta-analyses, systemic and narrative reviews, retrospective studies, as well as original studies on human and animal models. The results of these studies indicate a possible correlation between the different levels of micronutrients and a decreased risk of breast cancer as well as a better survival rate. However, further studies are necessary to establish adequate doses of supplementation of the chosen micronutrients and the exact mechanisms of micronutrient impact on breast cancer therapy.
... 38 DHRS3 amplification has been negatively associated with several cancers, such as triple-negative breast cancer and papillary thyroid carcinomas. [39][40][41] In our study, CG9265 was found to be overexpressed and its knockdown partially rescued the BCR::ABL T315I flies but had no effect on the BCR::ABL P210 flies. Although we currently lack a clear explanation for these findings, the observed partial rescue suggests that CG9265 plays a role and represents a potential target that requires further investigation. ...
Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder resulting from a balanced translocation leading to BCR::ABL1 oncogene with increased tyrosine kinase activity. Despite the advancements in the development of tyrosine kinase inhibitors (TKIs), the T315I gatekeeper point mutation in the BCR::ABL1 gene remains a challenge. We have previously reported in a Drosophila CML model an increased hemocyte count and disruption in sessile hemocyte patterns upon expression of BCR::ABL1p210 and BCR::ABL1T315I in the hemolymph. In this study, we performed RNA sequencing to determine if there is a distinct gene expression that distinguishes BCR::ABL1p210 and BCR::ABL1T315I. We identified six genes that were consistently upregulated in the fly CML model and validated in adult and pediatric CML patients and in a mouse cell line expressing BCR::ABL1T315I. This study provides a comprehensive analysis of gene signatures in BCR::ABL1p210 and BCR::ABL1T315I, laying the groundwork for targeted investigations into the role of these genes in CML pathogenesis.
... Also, in the datasets of project PRJNA573631 [55,56], only the 5 -tRH with length 33 nts from trna116_GluCTC shows higher abundance than its counterpart trna11_GluTTC. Lastly, note the similarities and differences in the 5 -tRHs and long 5 -tRFs that are produced from trna116_GluCTC and trna11_GluTTC in the MDA-MB-231 datasets of projects PR-JNA656851 [57], PRJNA672909 [58], and PRJNA700839 [59]. Figures 2 and 4 showed cases of tRFs where the relative and absolute tRF abundance varied between tissue samples and cell lines from the same tissue. ...
Transfer RNA-derived fragments (tRFs) are noncoding RNAs that arise from either mature transfer RNAs (tRNAs) or their precursors. One important category of tRFs comprises the tRNA halves, which are generated through cleavage at the anticodon. A given tRNA typically gives rise to several co-expressed 5’-tRNA halves (5′-tRHs) that differ in the location of their 3′ ends. These 5′-tRHs, even though distinct, have traditionally been treated as indistinguishable from one another due to their near-identical sequences and lengths. We focused on co-expressed 5′-tRHs that arise from the same tRNA and systematically examined their exact sequences and abundances across 10 different human tissues. To this end, we manually curated and analyzed several hundred human RNA-seq datasets from NCBI’s Sequence Run Archive (SRA). We grouped datasets from the same tissue into their own collection and examined each group separately. We found that a given tRNA produces different groups of co-expressed 5′-tRHs in different tissues, different cell lines, and different diseases. Importantly, the co-expressed 5′-tRHs differ in their sequences, absolute abundances, and relative abundances, even among tRNAs with near-identical sequences from the same isodecoder or isoacceptor group. The findings suggest that co-expressed 5′-tRHs that are produced from the same tRNA or closely related tRNAs have distinct, context-dependent roles. Moreover, our analyses show that cell lines modeling the same tissue type and disease may not be interchangeable when it comes to experimenting with tRFs.
... In light of the important role of the retinoid signaling pathway in bladder cancer, restoring retinoid function could be a potential therapeutic option to prevent and treat bladder cancer. The different signal transduction pathways in retinoids have been shown to interfere with cell cycle progression in a variety of human cancer cells, particularly by regulating cyclins, CDKs, and cell cycle inhibitors (63,64). Wang et al. (65) co-cultured RA with bladder cancer cells EJ and found that RA could significantly inhibit the growth of bladder cancer cells and reduce the expression of mutant P53 in cells. ...
Vitamin A has long been associated with bladder cancer, and many exogenous vitamin A supplements, vitamin A derivatives, and synthetic drugs have been investigated over the years. However, the effectiveness of these strategies in clinical practice has not met expectations, and they have not been widely adopted. Recent medical research on intestinal flora has revealed that bladder cancer patients exhibit reduced serum vitamin A levels and an imbalance of gut microbiota. In light of the close relationship between gut microbiota and vitamin A, one can speculate that a complex regulatory mechanism exists between the two in the development and occurrence of bladder cancer. As such, further exploration of their interaction in bladder cancer may help guide the use of vitamin A for preventive purposes. During the course of this review, attention is paid to the influence of intestinal microbiota on the vitamin A metabolism and the RA signaling pathway, as well as the mutual promotion relationships between them in the prevention of bladder cancer, In addition, it emphasizes the importance of intestinal microbiota for bladder cancer prevention and treatment.
... RARA has been reported to promote tumor progression in breast cancer (63), acute promyeloid leukemia (64), and liver cancer (65). In our study, the methylation level of the promoter (prmtr.27493) of RARA in HCC was significantly decreased, with the increase of promoter activity (65,66). ...
Background
The alternative usage of promoters provides a way to regulate gene expression, has a significant influence on the transcriptome, and contributes to the cellular transformation of cancer. However, the function of alternative promoters (APs) in hepatocellular carcinoma (HCC) has not been systematically studied yet. In addition, the potential mechanism of regulation to the usage of APs remains unclear. DNA methylation, one of the most aberrant epigenetic modifications in cancers, is known to regulate transcriptional activity. Whether DNA methylation regulates the usage of APs needs to be explored. Here, we aim to investigate the effects of DNA methylation on usage of APs in HCC.
Methods
Promoter activities were calculated based on RNA-seq data. Functional enrichment analysis was implemented to conduct GO terms. Correlation tests were used to detect the correlation between promoter activity and methylation status. The LASSO regression model was used to generate a diagnostic model. Kaplan–Meier analysis was used to compare the overall survival between high and low methylation groups. RNA-seq and whole-genome bisulfite sequencing (WGBS) in HCC samples were performed to validate the correlation of promoter activity and methylation.
Results
We identified 855 APs in total, which could be well used to distinguish cancer from normal samples. The correlation of promoter activity and DNA methylation in APs was observed, and the APs with negative correlation were defined as methylation-regulated APs (mrAPs). Six mrAPs were identified to generate a diagnostic model with good performance (AUC = 0.97). Notably, the majority of mrAPs had CpG sites that could be used to predict clinical outcomes by methylation status. Finally, we verified 85.6% of promoter activity variation and 92.3% of methylation changes in our paired RNA-seq and WGBS samples, respectively. The negative correlation between promoter activity and methylation status was further confirmed in our HCC samples.
Conclusion
The aberrant methylation status plays a critical role in the precision usage of APs in HCC, which sheds light on the mechanism of cancer development and provides a new insight into cancer screening and treatment.
... Using the online tool Kaplan Meier Plotter, we found no correlation between the expression level of RARα and overall patient survival (Fig. 1A). Since a study has shown that RARα is hyperphosphorylated in TNBC patient specimens [17], we next investigated whether forced hypophosphorylation of RARα will inhibit TNBC progression. We therefore (Fig. 1C). ...
... instead of RARα to promote cell proliferation [28]. Of note, previously we reported that RARαS77A reduced cell viability at later time points (24 h and above) [17]. ...
Retinoic acid receptor ? (RAR?) is a transcription factor that plays an essential role in tumor progression. Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma with a poor prognosis due to early therapeutic escape from conventional treatments and aggressive metastatic relapse by the occurrence of an epithelial-mesenchymal transition (EMT). However, as the expression level of RAR? does not correlate with the overall survival of TNBC patients, we speculate that post-translational modification such as phosphorylation of RAR? may be involved in EMT and TNBC metastasis. After overexpressing a phosphorylation-defective mutant of RAR? at serine 77 residue (RAR?S77A), we found that RAR? hypophosphorylation inhibited MDA-MB-231 cell motility and migration in vitro while reducing the lung metastatic potential in vivo. This was accompanied by increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers ?-catenin and zinc finger E-box-binding homeobox 1 (ZEB1) in agreement with the suppression of EMT. Interestingly, the overexpression of wild-type RAR? in the presence of the RAR? agonist AM580 failed to suppress EMT and cell migration. These results indicate that hypophosphorylated RAR?S77 can directly mimic activated RAR? to inhibit EMT and migration/invasion of cells, thus providing a novel target in the therapeutic intervention of TNBC.
... One other study remarks the impact of miR-374c-5p on apoptosis, controlling the proliferation, migration, epithelial-mesenchymal transition and apoptosis of human breast cancer cells, via repression of TATA box-binding protein associated 7 (TAF7) and expression of DEP domain containing 1 (DEPDC1), a transcriptional co-repressor involved in the promotion of carcinogenesis [166]. The tumour suppressive sequence miR-3074-5p has also been linked with increased apoptosis in both trophoblasts and breast cancer [167,168], but no direct reports link this sequence with altered lipid metabolism. By contrast, a number of recent studies cite both positive and negatives roles for miR-375 in apoptosis, of chrondocytes, breast, colon, gastric and hepatic cancer cells and cardiomyocytes [169][170][171][172][173][174][175][176]. ...
Alterations in lipid metabolism within beta cells and islets contributes to dysfunction and apoptosis of beta cells, leading to loss of insulin secretion and the onset of type 2 diabetes. Over the last decade, there has been an explosion of interest in understanding the landscape of gene expression which influences beta cell function, including the importance of small non-coding microRNA sequences in this context. This review sought to identify the microRNA sequences regulated by metabolic challenges in beta cells and islets, their targets, highlight their function and assess their possible relevance as biomarkers of disease progression in diabetic individuals. Predictive analysis was used to explore networks of genes targeted by these microRNA sequences, which may offer new therapeutic strategies to protect beta cell function and delay the onset of type 2 diabetes.
Breast cancer (BC) formation is primarily influenced by genetics, epigenetics and environmental factors. Aberrant Genetics and epigenetics leads to a condition known as heterogeneity. The heterogeneity of BC can be divided into several subtypes. Among the epigenetic factors, microRNAs (miRNAs) have been shown to play a crucial role in the development and progression of malignancies. These small non-coding RNAs regulate gene expression through a variety of mechanisms, resulting in either mRNA degradation or translation repression. As miRNAs directly control many proteins, genetic anomalies affect tumor metastasis, apoptosis, proliferation, and cell transportation. Consequently, miRNA dysregulations contribute not only in cancer development but also in invasiveness, proliferation rate and more importantly, drug response. Findings mostly indicate subtype-specified identical miRNA profile in BC. Among the BC subtypes, TNBC, HER2 + and luminal are the most resistant to therapy, respectively. Therapy resistance is greatly associated with miRNA expression profile. Hence, concentration of miRNA is the first marker of its role in chemotherapy response. Overexpressed miRNAs may disrupt drug efflux transporters and decrease the drug accumulation in cell. While down-regulated miRNAs which mediate drug resistance processes are mostly correlated with poor treatment response. Moreover, other mechanisms in which miRNAs play crucial roles in chemoresistance such as cell receptor mediations, dysregulation by environmental factors, DNA defects, etc. Recently, several miRNA-based treatments have shown promising results in cancer treatment. Inhibition of up-regulated miRNAs is one of these therapeutic approaches whilst transfecting cell with down-regulated miRNAs also show promising results. Moreover, drug-resistance could also be determined while in the pre-treatment phase via expression levels of miRNAs. Therefore, miRNAs provide intriguing insights and challenges in overcoming chemoresistance. In this article, we have discussed how miRNAs regulate breast cancer subtypes-specific chemoresistance.
