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Cancer is a complex genetic disorder characterized by abnormalities in both coding and regulatory non-coding RNAs. microRNAs (miRNAs) are key regulatory non-coding RNAs that modulate cancer development, functioning as both tumor suppressors and oncogenes. miRNAs play critical roles in cancer progression, influencing key processes such as initiation, promotion, and metastasis. They exert their effects by targeting tumor suppressor genes, thereby facilitating cancer progression, while also inhibiting oncogenes to prevent further disease advancement. The miR-10 family, particularly miR-10a-5p and miR-10b-5p (miR-10a/b-5p), is notably involved in cancer progression. Intriguingly, their functions can differ across different cancers, sometimes promoting and at other times suppressing tumor growth depending on the cancer type and target genes. This review explores the dual roles of miR-10a/b-5p as tumor-suppressive miRNAs (TSmiRs) or oncogenic miRNAs (oncomiRs) in various cancers by examining their molecular and cellular mechanisms and their impact on the tumor microenvironment. Furthermore, we discuss the potential of miR-10a/b-5p as therapeutic targets, emphasizing miRNA-based strategies for cancer treatment. The insights discussed in this review aim to advance our understanding of miR-10a/b-5p's roles in tumor biology and their application in developing innovative cancer therapies. [ABSTRACT FROM AUTHOR]

Gender and biological sex have distinct impacts on the pathogenesis of type 2 diabetes (T2D). Estrogen deficiency is known to predispose female mice to T2D. In our previous study, we found that a high-fat, high-sucrose diet (HFHSD) induces T2D in male mice through the miR-10b-5p/KLF11/KIT pathway, but not in females, highlighting hormonal disparities in T2D susceptibility. However, the underlying molecular mechanisms of this hormonal protection in females remain elusive. To address this knowledge gap, we utilized ovariectomized, estrogen-deficient female mice, fed them a HFHSD to induce T2D, and investigated the molecular mechanisms involved in estrogen-deficient diabetic female mice, relevant cell lines, and female T2D patients. Initially, female mice fed a HFHSD exhibited a delayed onset of T2D, but ovariectomy-induced estrogen deficiency promptly precipitated T2D without delay. Intriguingly, insulin (INS) was upregulated, while insulin receptor (INSR) and protein kinase B (AKT) were downregulated in these estrogen-deficient diabetic female mice, indicating insulin-resistant T2D. These dysregulations of INS, INSR, and AKT were mediated by a miR-10a/b-5p-NCOR2 axis. Treatment with miR-10a/b-5p effectively alleviated hyperglycemia in estrogen-deficient T2D female mice, while β-estradiol temporarily reduced hyperglycemia. Consistent with the murine findings, plasma samples from female T2D patients exhibited significant reductions in miR-10a/b-5p, estrogen, and INSR, but increased insulin levels. Our findings suggest that estrogen protects against insulin-resistant T2D in females through miR-10a/b-5p/NCOR2 pathway, indicating the potential therapeutic benefits of miR-10a/b-5p restoration in female T2D management. [ABSTRACT FROM AUTHOR]

Specific functions of interstitial cells of Cajal (ICC) have been linked to distinct classes that differ by morphology and distribution. In the small intestine, slow wave-generating ICC are located in the myenteric region (ICC-MY), whereas ICC that mediate neuromuscular neurotransmission occur either throughout the circular muscle layer (intramuscular ICC, ICC-IM) or in association with the deep muscular plexus (ICC-DMP). Selective isolation of ICC to characterize specific properties has been difficult. Recently, neurokinin-1 receptors have been detected in murine ICC-DMP and neurons but not in ICC-MY. Here we identified and isolated ICC-DMP/IM by receptor-mediated internalization of fluorescent substance P and Kit immunofluorescence. Specificity of labeling was verified by confocal microscopy. Mouse and human ICC-DMP/IM were detected in suspension by fluorescent microscopy and harvested for RT-PCR with micropipettes. The isolated cells expressed Kit but not markers for neurons, smooth muscle, or antigen-presenting cells. ICC-DMP expressed neurokinin-1 receptor, [M.sub.2] and M3 muscarinic receptors, P2[Y.sub.1] and P2[Y.sub.4] purinergic receptors, VIP receptor 2, soluble guanylate cyclase-1 subunits, and protein kinase G. L- or T-type [Ca.sup.2+] channels were not detected in these cells. ICC-MY and ICC-DMP were simultaneously detected and enumerated by flow cytometry and sorted to purity by fluorescence-activated cell sorting. In summary, functional classes of ICC have distinct molecular identities that can be used to selectively identify and harvest these cells with, for example, receptor-mediated uptake of substance P and Kit immunofluorescence. ICC-DMP express neurotransmitter receptors and signaling intermediate molecules that are consistent with their role in neuromuscular neurotransmission. Kit; substance P; neurokinin-1 receptor; flow cytometry; RT-PCR

ATP is proposed to be a major inhibitory neurotransmitter in the gastrointestinal (GI) tract, causing hyperpolarization and smooth muscle relaxation. ATP activates small-conductance [Ca.sup.2+]-activated [K.sup.+] channels that are involved in setting the resting membrane potential and causing inhibitory junction potentials. No reports are available examining the effects of ATP on voltage-dependent inward currents in GI smooth muscle cells. We previously reported two types of voltage-dependent inward currents in murine proximal colonic myocytes: a low-threshold voltage-activated, nonselective cation current ([I.sub.VNSCC]) and a relatively high-threshold voltage-activated (L-type) [Ca.sup.2+] current ([I.sub.L). Here we have investigated the effects of ATP on these currents. External application of ATP (1 mM) did not affect [I.sub.VNSCC] or [I.sub.L] in dialyzed cells. ATP (1 mM) increased [I.sub.VNSCC] and decreased 1L in the perforated whole-cell configuration. UTP and UDP (1 mM) were more potent than ATP on [I.sub.VNSCC]. ADP decreased [I.sub.L] but had no effect on [I.sub.VNSCC]. The order of effectiveness was UTP = UDP > ATP > ADP. These effects were not blocked by pyridoxal phosphate-6-azo(benzene-2, 4-disulfonic acid) (PPADS), but the phospholipase C inhibitor U-73122 reversed the effects of ATP on [I.sub.VNSCC]. ATP stimulation of [I.sub.VNSCC] was also reversed by protein kinase C (PKC) inhibitors chelerythrine chloride or bisindolylmaleimide I. Phorbol 12,13-dibutyrate mimicked the effects of ATP. RT-PCR showed that [P2Y.sub.4] is expressed by routine colonic myocytes, and this receptor is relatively insensitive to PPADS. Our data suggest that ATP activates [I.sub.VNSCC] and depresses [I.sub.L] via binding of [P2Y.sub.4] receptors and stimulation of the phospholipase C/PKC pathway. inhibitory junction potentials; smooth muscle; enteric nervous system

It has been assumed that in piebald lethal mice that develop megacolon, impaired colonic motor activity is restricted to the aganglionic distal colon. Peristaltic mechanical recordings, immunohistochemistry, and quantitative PCR were used to investigate whether regions of the colon, other than the aganglionic segment, may also show anatomical modifications and dysfunctional colonic motor activity. Contrary to expectations, colonic migrating motor complexes (MMCs) were absent along the whole colon of piebald lethal homozygote mice and severely impaired in heterozygote siblings. Aganglionosis was detected not only in the distal colon of piebald homozygote lethal mice (mean length: 20.4 [+ or -] 2.1 mm) but also surprisingly in their heterozygote siblings (mean length: 12.4 [+ or -] 1.1 mm). Unlike homozygote lethal mice, piebald heterozygotes showed no signs of megacolon. Interestingly, mRNA expression for PGP 9.5 was also dramatically reduced (by 71-99%) throughout the entire small and large bowel in both homozygote lethal and heterozygous littermates (by 67-87%). Histochemical staining confirmed a significant reduction in myenteric ganglia along the whole colon. In summary, the piebald mutation in homozygote lethal and heterozygote siblings is associated with dramatic reductions in myenteric ganglia throughout the entire colon and not limited to the distal colon as originally thought. Functionally, this results in an absence or severe impairment of colonic MMC activity in both piebald homozygote lethal and heterozygote siblings, respectively. The observation that piebald heterozygotes have an aganglionic distal colon (mean length: 12 mm) but live a normal murine life span without megacolon suggests that aganglionosis >12 mm and the complete absence of colonic MMCs may be required before any symptoms of megacolon arise. migrating motor complex; endothelin B receptor