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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]

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]

Long non-coding RNA (lncRNA), which is a kind of noncoding RNA, is generally characterized as being more than 200 nucleotide transcripts in length. LncRNAs exhibit many biological activities, including, but not limited to, cancer development. In this review, a search of the PubMed database was performed to identify relevant studies published in English. The term "lncRNA or long non-coding RNA" was combined with a range of search terms related to the core focus of the review: mechanism, structure, regulation, and cancer. The eligibility of the retrieved studies was mainly based on the abstract. The decision as to whether or not the study was included in this review was made after a careful assessment of its content. The reference lists were also checked to identify any other study that could be relevant to this review. We first summarized the molecular mechanisms of lncRNAs in tumorigenesis, including competing endogenous RNA (ceRNA) mechanisms, epigenetic regulation, decoy and scaffold mechanisms, mRNA and protein stability regulation, transcriptional and translational regulation, miRNA processing regulation, and the architectural role of lncRNAs, which will help a broad audience better understand how lncRNAs work in cancer. Second, we introduced recent studies to elucidate the structure of lncRNAs, as there is a link between lncRNA structure and function and visualizing the architectural domains of lncRNAs is vital to understanding their function. Third, we explored emerging evidence for regulators of lncRNA expression, lncRNA turnover, and lncRNA modifications (including 5-methylcytidine, N6-methyladenosine, and adenosine to inosine editing), highlighting the dynamics of lncRNAs. Finally, we used autophagy in cancer as an example to interpret the diverse mechanisms of lncRNAs and introduced clinical trials of lncRNA-based cancer therapies. [ABSTRACT FROM AUTHOR]