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Background: Previous studies have revealed that miR-26a-5p and miR-26b-5p act as tumour suppressors in various types of cancer tissues. Here, we aimed to investigate the functional roles of these miRNAs and to identify their regulatory targets in bladder cancer (BC). Methods: We performed functional assays in BC cells using transfection of mature microRNAs (miRNAs). In silico and luciferase reporter analyses were applied to identify target genes of these miRNAs. The overall survival (OS) of patients with BC was evaluated by the Kaplan–Meier method. Results: miR-26a-5p and miR-26b-5p were significantly downregulated in BC tissues. Restoration of these miRNAs inhibited cell migration and invasion in BC. The gene encoding procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 ( PLOD2 ), a collagen crosslinking enzyme, was directly regulated by miR-26a-5p and miR-26b-5p . Kaplan–Meier analysis revealed that patients with high PLOD2 expression had significantly shorter OS compared with those with low PLOD2 expression ( P =0.0153). Conclusions: PLOD2 , which is associated with the stiffness of the extracellular matrix, was directly regulated by miR-26a-5p and miR-26b-5p and may be a good prognostic marker in patients with BC.

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development 1 – 3 . However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient’s early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1 -mutated founder. Taken together, our findings provide new insight into how breast cancer evolves. By using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, unique evolutionary histories of breast cancers harbouring a common driver alteration are shown, providing new insight into how breast cancer evolves.

Clonal hematopoiesis (CH) in apparently healthy individuals is implicated in the development of hematological malignancies (HM) and cardiovascular diseases. Previous studies of CH analyzed either single-nucleotide variants and indels (SNVs/indels) or copy number alterations (CNAs), but not both. Here, using a combination of targeted sequencing of 23 CH-related genes and array-based CNA detection of blood-derived DNA, we have delineated the landscape of CH-related SNVs/indels and CNAs in 11,234 individuals without HM from the BioBank Japan cohort, including 672 individuals with subsequent HM development, and studied the effects of these somatic alterations on mortality from HM and cardiovascular disease, as well as on hematological and cardiovascular phenotypes. The total number of both types of CH-related lesions and their clone size positively correlated with blood count abnormalities and mortality from HM. CH-related SNVs/indels and CNAs exhibited statistically significant co-occurrence in the same individuals. In particular, co-occurrence of SNVs/indels and CNAs affecting DNMT3A , TET2 , JAK2 and TP53 resulted in biallelic alterations of these genes and was associated with higher HM mortality. Co-occurrence of SNVs/indels and CNAs also modulated risks for cardiovascular mortality. These findings highlight the importance of detecting both SNVs/indels and CNAs in the evaluation of CH. Analysis of single-nucleotide variants and copy number alterations gives a more complete picture of clonal hematopoiesis and its impact on hematological malignancy and cardiovascular disease.

Background: MicroRNAs (miRNAs) have been shown to play major roles in carcinogenesis in a variety of cancers. The aim of this study was to determine the miRNA expression signature of oral squamous cell carcinoma (OSCC) and to investigate the functional roles of miR-26a and miR-26b in OSCC cells. Methods: An OSCC miRNA signature was constructed by PCR-based array methods. Functional studies of differentially expressed miRNAs were performed to investigate cell proliferation, migration, and invasion in OSCC cells. In silico database and genome-wide gene expression analyses were performed to identify molecular targets and pathways mediated by miR-26a/b . Results: miR-26a and miR-26b were significantly downregulated in OSCC. Restoration of both miR-26a and miR-26b in cancer cell lines revealed that these miRNAs significantly inhibited cancer cell migration and invasion. Our data demonstrated that the novel transmembrane TMEM184B gene was a direct target of miR-26a/b regulation. Silencing of TMEM184B inhibited cancer cell migration and invasion, and regulated the actin cytoskeleton-pathway related genes. Conclusions: Loss of tumour-suppressive miR-26a/b enhanced cancer cell migration and invasion in OSCC through direct regulation of TMEM184B . Our data describing pathways regulated by tumour-suppressive miR-26a/b provide new insights into the potential mechanisms of OSCC oncogenesis and metastasis.

Carbon and other volatiles are transported from Earth’s surface into the mantle at subduction margins. The efficiency of this transfer has profound implications for the nature and scale of geochemical heterogeneities in Earth’s deep (mantle) and shallow (crustal) reservoirs, as well as Earth’s oxidation state. However, the proportion of volatiles released in the forearc and backarc are not well constrained compared to fluxes from the volcanic front. Here, we use helium and carbon isotope data from deeply sourced springs along two cross-arc transects to show that ~91% of carbon released from the slab/mantle beneath the Costa Rica forearc is sequestered within the crust by calcite deposition, and an additional ~3% is incorporated into biomass through microbial chemolithoautotrophy. We estimate that ~1.2 × 10(exp 8) to 1.3 × 10(exp 10) mol CO2/yr are released from the slab beneath the forearc, resulting in up to ~19% less carbon being transferred to Earth’s deep mantle than previously estimated.

Background: On the base of the microRNA (miRNA) expression signature of bladder cancer (BC), we found that miR-1 and miR-133a were significantly downregulated in BC. In this study, we focussed on the functional significance of miR-1 and miR-133a in BC cell lines and identified a molecular network of these miRNAs. Methods and results: We investigated the miRNA expression signature of BC clinical specimens and identified several downregulated miRNAs ( miR-133a , miR-204 , miR-1 , miR-139-5p , and miR-370 ). MiR-1 and miR-133a showed potential role of tumour suppressors by functional analyses of BC cells such as cell proliferation, apoptosis, migration, and invasion assays. Molecular target searches of these miRNAs showed that transgelin 2 ( TAGLN2 ) was directly regulated by both miR-1 and miR-133a . Silencing of TAGLN2 study demonstrated significant inhibitions of cell proliferation and increase of apoptosis in BC cell lines. The immunohistochemistry showed a positive correlation between TAGLN2 expression and tumour grade in clinical BC specimens. Conclusions: The downregulation of miR-1 and miR-133a was a frequent event in BC, and these miRNAs were recognised as tumour suppressive. TAGLN2 may be a target of both miRNAs and had a potential oncogenic function. Therefore, novel molecular networks provided by miRNAs may provide new insights into the underlying molecular mechanisms of BC.

Background: We have recently identified down-regulated microRNAs including miR-145 and miR-133a in bladder cancer (BC). The aim of this study is to determine the genes targeted by miR-145 , which is the most down-regulated microRNA in BC. Methods: We focused on fascin homologue 1 ( FSCN1 ) from the gene expression profile in miR-145 transfectant. The luciferase assay was used to confirm the actual binding sites of FSCN1 mRNA. Cell viability was evaluated by cell growth, wound-healing, and matrigel invasion assays. BC specimens were subjected to immunohistochemistry of FSCN1 and in situ hybridisation of miR-145 . Results: The miR-133a as well as miR-145 had the target sequence of FSCN1 mRNA by the database search, and both microRNAs repressed the mRNA and protein expression of FSCN1. The luciferase assay revealed that miR-145 and miR-133a were directly bound to FSCN1 mRNA. Cell viability was significantly inhibited in miR-145 , miR-133a , and si-FSCN1 transfectants. In situ hybridisation revealed that miR-145 expression was markedly repressed in the tumour lesion in which FSCN1 was strongly stained. The immunohistochemical score of FSCN1 in invasive BC ( n =46) was significantly higher than in non-invasive BC ( n =20) ( P =0.0055). Conclusion: Tumour suppressive miR-145 and miR-133a directly control oncogenic FSCN1 in BC.

Epidermoid lesions account for 1% of intracranial neoplasms. Surgical management is challenging due to their adhesion to critical neurovascular structures and tendency for recurrence. The current study examines surgical outcomes, extent of resection, and recurrence rates during long-term follow-up. A retrospective analysis was conducted on patients treated for epidermoid lesions between 2000 and 2021, focusing on clinical and radiological outcome and long-term symptom development. Among 55 patients (56.4% male), the majority harbored lesions in the cerebellopontine angle (75.3%). The mean age at surgery was 41.3 years, with an average follow-up of 82 months. Total removal was achieved in 61% of cases, with 75% of them remaining recurrence-free. In comparison, 35% of near-total removal and 25% of subtotal removal remained recurrence-free. Immediate symptom improvement was similar after total and non-total removal (12.6% vs. 10.5%), but long-term improvement was higher after total removal (43% vs. 27%). Transient cranial nerve deficits occurred in 25% of total and in 32% of non-total removal cases, with similar rates of minor complications. Total removal provided better long-term symptom control and lower recurrence rates without significantly increasing neurological deficits, supporting it as the preferred surgical strategy while maintaining functional preservation.

Bile duct cancer (BDC) frequently invades the nerve fibers, making complete surgical resection difficult. A single tumor mass contains cells of variable malignancy and cell‐differentiation states, with cancer stem cells (CSCs) considered responsible for poor clinical outcomes. This study aimed to investigate the contribution of autosynthesized dopamine to CSC‐related properties in BDC. Sphere formation assays using 13 commercially available BDC cell lines demonstrated that blocking dopamine receptor D1 (DRD1) signaling promoted CSC‐related anchorage‐independent growth. Additionally, we newly established four new BDC patient‐derived organoids (PDOs) and found that blocking DRD1 increased resistance to chemotherapy and enabled xenotransplantation in vivo. Single‐cell analysis revealed that the BDC PDO cells varied in their cell‐differentiation states and responses to dopamine signaling. Further, DRD1 inhibition increased WNT7B expression in cells with bile duct‐like phenotype, and it induced proliferation of other cell types expressing Wnt receptors and stem cell‐like signatures. Reagents that inhibited Wnt function canceled the effect of DRD1 inhibition and reduced cell proliferation in BDC PDOs. In summary, in BDCs, DRD1 is a crucial protein involved in autonomous CSC proliferation through the regulation of endogenous WNT7B. As such, inhibition of the DRD1 feedback signaling may be a potential treatment strategy for BDC. Single‐cell analysis revealed that the Bile duct cancer patient‐derived organoid cells varied in their cell‐differentiation states and responses to their autosynthesized dopamine. Further, DRD1 inhibition increased WNT7B expression in cells with bile duct‐like phenotype, and it induced proliferation of other cell types expressing Wnt receptors and stem cell‐like signatures.

Background: Analysis of a microRNA (miRNA) expression signature of bladder cancer (BC) by deep-sequencing revealed that clustered miRNAs microRNA ( miR ) -451a , miR-144-3p , and miR-144-5p were significantly downregulated in BC tissues. We hypothesised that these miRNAs function as tumour suppressors in BC. The aim of this study was to investigate the functional roles of these miRNAs and their modulation of cancer networks in BC cells. Methods: The functional studies of BC cells were performed using transfection of mature miRNAs. Genome-wide gene expression analysis, in silico analysis, and dual-luciferase reporter assays were applied to identify miRNA targets. The association between miR-144-5p levels and expression of the target genes was determined, and overall patient survival as a function of target gene expression was estimated by the Kaplan–Meier method. Results: Gain-of-function studies showed that miR-144-5p significantly inhibited cell proliferation by BC cells. Four cell cycle-related genes ( CCNE1 , CCNE2 , CDC25A , and PKMYT1 ) were identified as direct targets of miR-144-5p . The patients with high CCNE1 or CCNE2 expression had lower overall survival probabilities than those with low expression ( P =0.025 and P =0.032). Conclusion: miR-144-5p functions as tumour suppressor in BC cells. CCNE1 and CCNE2 were directly regulated by miR-144-5p and might be good prognostic markers for survival of BC patients.