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Background Cancer associated fibroblasts (CAFs) can remodel tumor microenvironment by secreting exosomes. This study aimed to investigate the role of exosomes derived from cancer-associated fibroblasts in colorectal cancer (CRC) progression. Methods Circular RNA (circRNA) array was used to identify differentially expressed circRNAs in exosomes from normal fibroblasts (NFs) and CAFs, and confirmed one differentially expressed circRNA circ_0067557 by real-time PCR. The effect of circ_0067557 on proliferation, metastasis, chemoresistance and apoptosis was verified by wound heal, tranwell, CCK8, sphere-forming and flow cytometry assay. Results Circ_0067557 expression in exosomes from CAFs was higher than those from NFs. CAF-derived exosomes promoted the proliferation, migration, invasion and chemoresistance of CRC cells while suppressed apoptosis. Silencing of circ_0067557 inhibited malignant phenotypes of CRC cells by targeting Lin28A and Lin28B. Moreover, CAF-derived exosomes enhanced the growth of CRC xenograft tumors. Conclusion Circ_0067557/Lin28A and Lin28B signal axis may be a potential therapy target for CRC.

Chemoresistance has become a leading cause of mortality in breast cancer patients and is one of the major obstacles for improving the clinical outcome. Long noncoding RNAs play important roles in breast cancer tumorigenesis and chemoresistance. However, the involvement and regulation of lncRNAs in breast cancer chemoresistance are not completely understood. Here, we reported that Linc00839 was localized in the nucleus and upregulated in chemoresistant breast cancer cells and tissues, and high level of Linc00839 was associated with a poor prognosis. Knockdown of Linc00839 significantly suppressed proliferation, invasion, and migration, sensitized cells to paclitaxel in vitro and inhibited transplant tumor development in vivo. Mechanistically, we found that Myc could directly bind to the promoter region of Linc00839 and activate its transcription. Furthermore, Linc00839 overexpression increased the expression of Myc and the RNA‐binding protein Lin28B and activated the PI3K/AKT signaling pathway. We also discovered that Lin28B positively interacted with Linc00839 and was upregulated in breast cancer tissues. Taken together, for the first time, we showed that Linc00839 was activated by Myc and promoted proliferation and chemoresistance in breast cancer through binding with Lin28B. These findings provide new insight into the regulatory mechanism of Linc00839 and propose a Myc/Linc00839/Lin28B feedback loop that could be used as a novel therapeutic target for breast cancer. Linc00839 displayed a remarkable trend towards increasing expression levels in BC resistant cells and tissue samples. The upregulation of Linc00839 was transcriptionally activated by the crucial oncogene Myc, and it was able to regulate Myc and Lin28B protein expression. Linc00839 promoted cell proliferation and chemoresistance by enhancing the activity of the PI3K/AKT pathway.

LIN28B is highly expressed in neuroblastoma and promotes tumorigenesis, at least, in part, through inhibition of let-7 micro-RNA biogenesis. Here, we report that overexpression of either wild-type (WT) LIN28B or a LIN28B mutant that is unable to inhibit let-7 processing increases the penetrance of MYCN-induced neuroblastoma, potentiates the invasion and migration of transformed sympathetic neuroblasts, and drives distant metastases in vivo. Genome-wide chromatin immunoprecipitation coupled with massively parallel DNA sequencing (ChIP-seq) and coimmunoprecipitation experiments show that LIN28B binds active gene promoters in neuroblastoma cells through protein–protein interaction with the sequence-specific zinc-finger transcription factor ZNF143 and activates the expression of downstream targets, including transcription factors forming the adrenergic core regulatory circuitry that controls the malignant cell state in neuroblastoma as well as GSK3B and L1CAM that are involved in neuronal cell adhesion and migration. These findings reveal an unexpected let-7–independent function of LIN28B in transcriptional regulation during neuroblastoma pathogenesis.

Abstract Background Circular RNAs (circRNAs) could participate in cis-dichlorodiammineplatinum (DDP) resistance of human cancers. However, circRNAs role in DDP resistance of oral squamous cell carcinoma (OSCC) progression remains largely undeveloped. Here, we attempted to explore the role of circ-SCMH1 (ID hsa_(c)irc₀011946) in acquired DDP resistance. Methods Expression of circ-SCMH1, microRNA (miR)-338-3p and Lin-28 homolog B (LIN28B) was detected by real-time quantitative PCR and western blotting, and their interactions were confirmed by dual-luciferase reporter assay, RNA immunoprecipitation and RNA pull-down assay. DDP resistance was assessed by MTT assay, colony formation assay, flow cytometry, transwell assays, western blotting, and xenograft experiment. Transmission electron microscopic analysis, nanoparticle tracking analysis and western blotting confirmed the characterizations of extracellular vesicles (EVs). Results Circ-SCMH1 was upregulated in DDP-resistant OSCC tissues and cells (SCC-15/DDP and CAL-27/DDP). Circ-SCMH1 knockdown suppressed the half-maximal inhibitory concentration of DDP, colony formation, and migration/invasion in SCC-15/DDP and CAL-27/DDP cells, but promoted apoptosis rate and apoptotic proteins (Bax and cleaved-caspase-3) expression. However, silencing miR-338-3p abrogated above effects, and overexpressing miR-338-3p mimicked that. Similarly, miR-338-3p overexpression role could be counteracted by restoring LIN28B. Moreover, interfering circ-SCMH1 retarded tumor growth of SCC-15/DDP cells in vivo with DDP treatment or not. Mechanistically, circ-SCMH1 directly sponged miR-338-3p in regulating LIN28B, a target gene for miR-338-3p. Notably, circ-SCMH1 was an EVs cargo, and DDP-resistant OSCC cells-derived EVs could provoke circ-SCMH1 upregulation in parental cells. Conclusion Circ-SCMH1 contributes to chemoresistance of DDP-resistant OSCC cells partially via EVs secretion and circ-SCMH1/miR-338-3p/LIN28B axis.

Background The potential involvement of circular RNAs (circRNAs) and N 6 -methyladenosine (m 6 A) modification in the progression of Wilms tumor (WT) has not been fully elucidated. This study investigates the regulatory mechanisms and clinical significance of m 6 A-modified circMARK2 and its role in WT progression. Methods We identified dysregulated circRNAs through deep sequencing and validated their expression by qRT-PCR in WT tissues. The biological functions of circMARK2 were assessed using clone formation, transwell migration, and orthotopic animal models. To dissect the underlying mechanisms, we employed RNA immunoprecipitation, RNA pull-down, dual-luciferase reporter assays, Western blotting, and immunofluorescence and immunohistochemical staining. Results CircMARK2, upregulated in WT tissues, was found to be m 6 A-modified and promoted cytoplasmic export. It facilitated WT progression by stabilizing LIN28B mRNA through the circMARK2/IGF2BP2 interaction. In vitro and in vivo studies demonstrated that circMARK2 enhances the malignant behavior of WT cells. Clinically, higher circMARK2 levels in tumor tissues of WT patients were linked to increased tumor aggressiveness and reduced survival rates. Conclusions Our study provides the first comprehensive evidence that m 6 A-modified circMARK2 contributes to WT progression by enhancing LIN28B mRNA stability, promoting cellular aggressiveness. CircMARK2 emerges as a potential biomarker for prognosis and a promising target for therapeutic intervention in WT, underscoring the clinical relevance of m 6 A modification in pediatric renal cancer.

RNA binding proteins (RBPs) and microRNAs (miRNAs) are two of the most important post-transcriptional regulators of gene expression, and their aberrant expression contributes to the development of human malignancies. Let-7, one of the most well-known tumor suppressors, is frequently down-regulated in a variety of human cancers. The RBP LIN28A/LIN28B, a direct target of the let-7 family of miRNAs, is an inhibitor of let-7 biogenesis and is frequently up-regulated in cancers. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors is reportedly involved in cancer development, contributing to cellular proliferation, cell death resistance, angiogenesis, metastasis, metabolism reprogramming, tumor-associated inflammation, genome instability, acquiring immortality and evading immune destruction. In this review, we summarized the mechanisms of LIN28A/LIN28B and let-7 loop aberrant regulation in human cancer and discussed the roles and potential mechanisms of the LIN28A/LIN28B and let-7 loop in regulating the hallmarks of cancer. The crosstalk between LIN28A/LIN28B and let-7 loop and certain oncogenes (such as MYC, RAS, PI3K/AKT, NF-κB and β-catenin) in regulating hallmarks of cancer has also been discussed.

Cancer associated fibroblasts (CAFs) can remodel tumor microenvironment by secreting exosomes. This study aimed to investigate the role of exosomes derived from cancer-associated fibroblasts in colorectal cancer (CRC) progression. Circular RNA (circRNA) array was used to identify differentially expressed circRNAs in exosomes from normal fibroblasts (NFs) and CAFs, and confirmed one differentially expressed circRNA circ₀067557 by real-time PCR. The effect of circ₀067557 on proliferation, metastasis, chemoresistance and apoptosis was verified by wound heal, tranwell, CCK8, sphere-forming and flow cytometry assay. Circ₀067557 expression in exosomes from CAFs was higher than those from NFs. CAF-derived exosomes promoted the proliferation, migration, invasion and chemoresistance of CRC cells while suppressed apoptosis. Silencing of circ₀067557 inhibited malignant phenotypes of CRC cells by targeting Lin28A and Lin28B. Moreover, CAF-derived exosomes enhanced the growth of CRC xenograft tumors. Circ₀067557/Lin28A and Lin28B signal axis may be a potential therapy target for CRC.

Father absence has a small but robust association with earlier age at menarche (AAM), likely reflecting both genetic confounding and an environmental influence on life history strategy development. Studies that have attempted to disambiguate genetic versus environmental contributions to this association have shown conflicting findings, though genomic-based studies have begun to establish the role of gene–environment interplay in the father absence/AAM literature. The purpose of this study was to replicate and extend prior genomic work using the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective longitudinal cohort study (N = 2,685), by (a) testing if an AAM polygenic score (PGS) could account for the father absence/AAM association, (b) replicating G×E research on lin-28 homolog B (LIN28B) variation and father absence, and (c) testing the G×E hypothesis using the PGS. Results showed that the PGS could not explain the father absence/AAM association and there was no interaction between father absence and the PGS. Findings using LIN28B largely replicated prior work that showed LIN28B variants predicted later AAM in father-present girls, but this AAM-delaying effect was absent or reversed in father-absent girls. Findings are discussed in terms genetic confounding, the unique biological role of LIN28B, and using PGSs for G×E tests.

Single‐molecule techniques have been used for only a subset of biological problems because of difficulties in studying proteins that require cofactors or post‐translational modifications. Here, we present a new method integrating single‐molecule fluorescence microscopy and immunopurification to study protein complexes. We used this method to investigate Lin28‐mediated microRNA uridylation by TUT4 (terminal uridylyl transferase 4, polyU polymerase), which regulates let‐7 microRNA biogenesis. Our real‐time analysis of the uridylation by the TUT4 immunoprecipitates suggests that Lin28 functions as a processivity factor of TUT4. Our new technique, SIMPlex (single‐molecule approach to immunoprecipitated protein complexes), provides a universal tool to analyse complex proteins at the single‐molecule level. This study describes a single‐molecule immunoprecipitation method used to investigate the mechanisms of Lin28‐mediated miRNA uridylation. The method expands the scope of single‐molecule approaches to new and complex protein systems.

Male reproductive development starts early in the embryogenesis with somatic and germ cell differentiation in the testis. The LIN28 family of RNA-binding proteins promoting pluripotency has two members—LIN28A and LIN28B. Their function in the testis has been investigated but many questions about their exact role based on the expression patterns remain unclear. LIN28 expression is detected in the gonocytes and the migrating, mitotically active germ cells of the fetal testis. Postnatal expression of LIN28 A and B showed differential expression, with LIN28A expressed in the undifferentiated spermatogonia and LIN28B in the elongating spermatids and Leydig cells. LIN28 interferes with many signaling pathways, leading to cell proliferation, and it is involved in important testicular physiological processes, such as cell renewal, maturation, fertility, and aging. In addition, aberrant LIN28 expression is associated with testicular cancer and testicular disorders, such as hypogonadotropic hypogonadism and Klinefelter’s syndrome. This comprehensive review encompasses current knowledge of the function of LIN28 paralogs in testis and other tissues and cells because many studies suggest LIN28AB as a promising target for developing novel therapeutic agents.