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Simple Summary: tRF-27 has been identified as upregulated in both naïve trastuzumab-resistant HER2-positive breast cancer cells and patient samples, positioning it as a potential biomarker. However, the underlying mechanisms of this upregulation remain unclear. This study proposes that the abnormal transcription of specific tRNA-Cys-GCA isodecoders in naïve trastuzumab-resistant cells might contribute to the accumulation of tRF-27. Additionally, the reduction in H3K27me3 modifications at these tRNA genes, attributed to imbalances in histone modification enzymes, appears to influence tRNA transcription alterations. Building upon these findings, our research demonstrates that the application of a demethylase inhibitor may offer a potential strategy to overcome trastuzumab resistance. tRNA-derived fragments (tRFs) play crucial roles in cancer progression. Among them, tRF-27 has been identified as a key factor in promoting naïve trastuzumab resistance in HER2-positive breast cancer. However, the origin of tRF-27 remains uncertain. In this study, we propose that the upregulated expression of specific cysteine tRNAs may lead to the increased accumulation of tRF-27 in trastuzumab-resistant JIMT1 cells. Mechanistically, the reduced inhibitory H3K27me3 modification at the promoter regions of tRF-27-related tRNA genes in JIMT1 cells, potentially resulting from decreased EZH2 and increased KDM6A activity, may be a critical factor stimulating the transcriptional activity of these tRNA genes. Our research offers fresh insights into the mechanisms underlying elevated tRF-27 levels in trastuzumab-resistant breast cancer cells and suggests potential strategies to mitigate trastuzumab resistance in clinical treatments. [ABSTRACT FROM AUTHOR]

Arsenic (As) exposure has been a global public health concern for hundreds of millions worldwide. LncRNA APTR (Alu-mediated p21 transcriptional regulator) plays an essential role in tumor growth and development. However, its function in arsenic-induced toxicological responses is still unknown. In this study, we found that the expressions of all transcripts and the transcript NR 134251.1 of APTR were increased in a dose-dependent manner in 16HBE cells treated with sodium arsenite (NaAsO2). Silencing the transcript NR 134251.1 of APTR inhibited cell proliferation and induced apoptosis. However, silencing all transcripts of APTR had the opposite function to the transcript NR 134251.1. Then we examined the protein level of the proliferation and apoptosis-related genes after silencing the transcript NR 134251.1 of APTR. The results showed that silencing the transcript NR 134251.1 of APTR up-regulated the expression of transcription factor E2F1 and regulated its downstream genes involved in proliferation and apoptosis, including p53, phospho-p53-S392, phospho-p53-T55, p21, Cyclin D1, PUMA, Fas, Bim, BIK, Caspase-3, Caspase-7, and Cyt-c. In conclusion, arsenic induced APTR expression and the transcript NR 134251.1 of APTR have an opposite function to all transcripts, providing a theoretical basis for the prevention and treatment of arsenic exposure. [ABSTRACT FROM AUTHOR]

Background: Growing evidence demonstrated that long noncoding RNAs (lncRNAs) were involved in the progression of diverse cancers, including breast cancer (BC). Recent studies indicated that lncRNA nuclear enriched abundant transcript 1 (NEAT1) was overexpressed and facilitated tumor processes in many cancers. Nevertheless, the underlying mechanism of NEAT1 in regulating BC progression is still largely unknown. Materials and Methods: The abundance of NEAT1, microRNA-138-5p (miR-138-5p), and zinc finger protein X-linked (ZFX) was assessed by quantitative real-time polymerase chain reaction. Cell Counting Kit-8 (CCK-8) assay, flow cytometry, and transwell assay were utilized to evaluate cell proliferation, apoptosis, migration, and invasion, respectively. Western blot analysis was applied to detect the protein expression of CyclinD1, Bax, E-cadherin, and ZFX. The interaction between miR-138-5p and NEAT1 or ZFX was predicted by starBase v3.0 and validated by dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation assays. The mice xenograft model was established to investigate the roles of NEAT1 in vivo. Results:NEAT1 was highly expressed and miR-138-5p was lowly expressed in BC tissues and cells. NEAT1 interference or miR-138-5p restoration repressed cell proliferation, migration, and invasion but accelerated apoptosis in BC cells. Moreover, miR-138-5p directly interacted with NEAT1 and its knockdown reversed the suppressive impact of NEAT1 downregulation on the progression of BC cells. In addition, ZFX was a downstream target of miR-138-5p and its upregulation attenuated the antitumor role of miR-138-5p in BC cells. Besides, ZFX expression was positively regulated by NEAT1 and inversely modulated by miR-138-5p. Furthermore, interference of NEAT1 inhibited tumor growth by upregulating miR-138-5p and downregulating ZFX. Conclusion:NEAT1 affected BC progression through modulating miR-138-5p/ZFX axis, providing a vital theoretical basis for BC treatment. [ABSTRACT FROM AUTHOR]

Antler is the secondary sexual characteristic of deer, which develops on the forehead at puberty. It is the only organ that can be regenerated entirely in mammals. Therefore, it is often used as a research model in the field of organ regeneration and wound repair. Many growth factors and proteins play an active role throughout the developmental process of antler regeneration. With the rapid development of sequencing technology, more and more noncoding RNAs (ncRNAs) have been discovered, and the relationship between ncRNA and antler regeneration has gradually become clear. This paper focuses on the research progress of several ncRNAs (including miRNA and lncRNA) in deer antler tissues, which are helpful to reveal the molecular mechanism of deer antler regeneration at the molecular level. [ABSTRACT FROM AUTHOR]

Pancreatic β-cells adapt to compensate for increased metabolic demand during obesity. Although the miRNA pathway has an essential role in β-cell expansion, whether it is involved in adaptive proliferation is largely unknown. First, we report that EGR2 binding to the miR-455 promoter induced miR-455 upregulation in the pancreatic islets of obesity mouse models. Then, in vitro gain- or loss-of-function studies showed that miR-455 overexpression facilitated β-cell proliferation. Knockdown of miR-455 in ob/ob mice via pancreatic intraductal infusion prevented compensatory β-cell expansion. Mechanistically, our results revealed that increased miR-455 expression inhibits the expression of its target cytoplasmic polyadenylation element binding protein 1 (CPEB1), an mRNA binding protein that plays an important role in regulating insulin resistance and cell proliferation. Decreased CPEB1 expression inhibits elongation of the poly(A) tail and the subsequent translation of Cdkn1b mRNA, reducing the CDKN1B expression level and finally promoting β-cell proliferation. Taken together, our results show that the miR-455/CPEB1/CDKN1B pathway contributes to adaptive proliferation of β-cells to meet metabolic demand during obesity. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is closely related to the development of several malignancies, such as B-cell lymphoma (B-CL), by the mechanism through which these malignancies develop remains largely unknown. We previously observed downregulation of the long noncoding RNA (lncRNA) IGFBP7-AS1 in response to EBV infection. However, the role of IGFBP7-AS1 in EBV-associated cancers has not been clarified. Here, we found that expression of IGFBP7-AS1, as well as its sense gene IGFBP7, is decreased in EBV-positive B-CL cells and clinical tissues. IGFBP7-AS1 stabilizes IGFBP7 mRNA by forming a duplex based on their overlapping regions. The tumour suppressor p53 transcriptionally activates IGFBP7-AS1 expression by binding to the promoter region of the lncRNA gene. The IGFBP7-AS1 expression is able to be rescued in EBV-positive cells in wild-type (wt) p53-dependent manner. IGFBP7-AS1 inhibits the proliferation and promotes the apoptosis of B-CL cells. Moreover, tumorigenic properties due to the depletion of IGFBP7-AS1 were restored by exogenous expression of IGFBP7 or wt-p53. Furthermore, the functional p53/IGFBP7-AS1/IGFBP7 axis facilitates apoptosis by suppressing the production and secretion of the NPPB signal peptide and further regulating the cGMP-PKG signalling pathway. This study demonstrates that EBV promotes tumorigenesis, particularly in B-CL progression, by downregulating the novel p53-responsive lncRNA IGFBP7-AS1. [ABSTRACT FROM AUTHOR]

The nuclear transcription factor twist-related protein 1 (Twist1) is associated with tumor malignant transformation and metastasis in various types of carcinomas. We found that Twist1 was highly expressed in clinical multiple myeloma (MM) cells, and explored its roles in proliferation and apoptosis in human MM cell lines U266 and RPMI-8226. In these cells, Twist1 transcriptionally regulated the miRNA hsa-miR138-5p, which targeted caspase-3 to control apoptosis. Silencing of Twist1 significantly suppressed cell proliferation and increased apoptosis, which was reversed by overexpression of hsa-miR138-5p or simultaneous silencing of caspase-3. This reversion was further substantiated by attenuated apoptotic signaling, including downregulated expression of the cleaved forms of caspase-3 and peroxisome proliferator-activated receptor 1 (PPAR1). We demonstrate here for the first time that the novel Twist1/hsa-miR138-5p/caspase-3 pathway contributes significantly to the proliferation and survival of human MM cells. Our study provides new insight for novel MM treatments by developing Twist1-targeted therapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) ranks third for incidence and second for number of deaths among cancer types worldwide. Poor patient survival due to inadequate response to currently available treatment regimens points to the urgent requirement for personalized therapy in CRC patients. Our aim was to provide mechanistic insights into the pro-tumorigenic role of the RNA-binding protein ESRP1, which is highly expressed in a subset of CRC patients. We show that, in CRC cells, ESRP1 binds to and has the same trend in expression as RAC1b, a well-known tumor promoter. Thus, RAC1b may be a potential therapeutic target in ESRP1-overexpressing CRC. RNA binding proteins are well recognized as critical regulators of tumorigenic processes through their capacity to modulate RNA biogenesis, including alternative splicing, RNA stability and mRNA translation. The RNA binding protein Epithelial Splicing Regulatory Protein 1 (ESRP1) can act as a tumor suppressor or promoter in a cell type- and disease context-dependent manner. We have previously shown that elevated expression of ESRP1 in colorectal cancer cells can drive tumor progression. To gain further insights into the pro-tumorigenic mechanism of action of ESRP1, we performed cDNA microarray analysis on two colorectal cells lines modulated for ESRP1 expression. Intriguingly, RAC1b was highly expressed, both at mRNA and protein levels, in ESRP1-overexpressing cells, while the opposite trend was observed in ESRP1-silenced CRC cells. Moreover, RAC1 and RAC1b mRNA co-immunoprecipitate with ESRP1 protein. Silencing of RAC1b expression significantly reduced the number of soft agar colonies formed by ESRP1-overexpressing cells, suggesting that ESRP1 acted, at least partially, through RAC1b in its tumor-promoting activities in CRC cells. Thus, our data provide molecular cues on targetable candidates in CRC cases with high ESRP1 expression. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometriosis is a common gynecological condition that causes pelvic pain and infertility. Despite having normal histological features, several cells bear cancer-associated somatic mutations that result in local tissue invasion but rarely metastasize. Several cancer-associated genes, such as KRAS and PIK3CA, are frequently mutated in the endometriotic epithelium. However, the functional behavior and molecular pathogenesis of this disorder remain unclear. In this study, we developed an immortalized endometriotic epithelial cell line with mutations in KRAS and PIK3CA, which are genes associated with aggressive behaviors, such as increased cell migration, invasion, and proliferation. Through microarray analysis, the KRAS- and PIK3CA-specific gene signatures were identified; LOX and PTX3 were found to be responsible for this metastatic behavior. Knockdown of these two genes by siRNA markedly reduced the metastatic ability of the cells. Our findings suggest that inhibition of LOX and PTX3 may be an alternative therapeutic strategy to reduce the incidence of endometriosis. Endometriosis-harboring cancer-associated somatic mutations of PIK3CA and KRAS provides new opportunities for studying the multistep processes responsible for the functional and molecular changes in this disease. We aimed to establish a novel in vitro endometriosis model to clarify the functional behavior and molecular pathogenesis of this disorder. Immortalized HMOsisEC10 human ovarian endometriotic epithelial cell line was used in which KRAS and PIK3CA mutations were introduced. Migration, invasion, proliferation, and microarray analyses were performed using KRAS and PIK3CA mutant cell lines. In vitro assays showed that migration, invasion, and proliferation were significantly increased in KRAS and PIK3CA mutant cell lines, indicating that these mutations played causative roles in the aggressive behavior of endometriosis. Microarray analysis identified a cluster of gene signatures; among them, two significantly upregulated cancer-related genes, lysyl oxidase (LOX) and pentraxin3 (PTX3), were associated with cell proliferation, invasion, and migration capabilities. Furthermore, siRNA knockdown of the two genes markedly reduced the metastatic ability of the cells. These results suggest that endometriosis with KRAS or PIK3CA mutations can significantly enhance cell migration, invasion, and proliferation by upregulating LOX and PTX3. We propose that LOX and PTX3 silencing using small molecules could be an alternative therapeutic regimen for severe endometriosis. [ABSTRACT FROM AUTHOR]