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Unveiling the key pathways underlying postnatal beta-cell proliferation can be instrumental to decipher the mechanisms of beta-cell mass plasticity to increased physiological demand of insulin during weight gain and pregnancy. Using transcriptome and global Serine Threonine Kinase activity (STK) analyses of islets from newborn (10 days old) and adult rats, we found that highly proliferative neonatal rat islet cells display a substantially elevated activity of the mitogen activated protein 3 kinase 12, also called dual leucine zipper-bearing kinase (Dlk). As a key upstream component of the c-Jun amino terminal kinase (Jnk) pathway, Dlk overexpression was associated with increased Jnk3 activity and was mainly localized in the beta-cell cytoplasm. We provide the evidence that Dlk associates with and activates Jnk3, and that this cascade stimulates the expression of Ccnd1 and Ccnd2, two essential cyclins controlling postnatal beta-cell replication. Silencing of Dlk or of Jnk3 in neonatal islet cells dramatically hampered primary beta-cell replication and the expression of the two cyclins. Moreover, the expression of Dlk,Jnk3,Ccnd1 and Ccnd2 was induced in high replicative islet beta cells from ob/ob mice during weight gain, and from pregnant female rats. In human islets from non-diabetic obese individuals, DLK expression was also cytoplasmic and the rise of the mRNA level was associated with an increase of JNK3,CCND1andCCND2 mRNA levels, when compared to islets from lean and obese patients with diabetes. In conclusion, we find that activation of Jnk3 signalling by Dlk could be a key mechanism for adapting islet beta-cell mass during postnatal development and weight gain.

The molecular heterogeneity of renal cell carcinoma (RCC) complicates the therapeutic interventions for advanced metastatic disease and thus its management remains a significant challenge. This study investigates the role of the lncRNA CDKN2B-AS1 and miR-141-3p interactions in the progression and metastasis of kidney cancer. Human renal cancer cell lines (ACHN and Caki1), normal RPTEC cells, tissue cohorts, and a series of in vitro assays and in vivo mouse model were used for this study. An overexpression of CDKN2B-AS1 was observed in RCC compared to normal samples in TCGA and our in-house SFVAMC tissue cohorts. Reciprocally, we observed reduced expression of miR-141 in RCC compared to normal in the same cohorts. CDKN2B-AS1 shares regulatory miR-141 binding sites with CCND1 and CCND2 genes. Direct interactions of CDKN2B-AS1 /miR-141/Cyclin D1–D2 were confirmed by RNA immunoprecipitation and luciferase reporter assays indicating that CDKN2B-AS1 /miR-141/Cyclin D1–D2 acts as a ceRNA network in RCC. Functionally, attenuation of CDKN2B-AS1 and/or overexpression of miR-141 inhibited proliferation, clonogenicity, migration/invasion, induced apoptosis in vitro and suppressed tumor growth in xenograft mouse model. Further, overexpression of CDKN2B-AS1 is positively correlated with poor overall survival of RCC patients. Expression of miR-141 also robustly discriminated malignant from non-malignant tissues and its inhibition in normal RPTEC cells induced pro-cancerous characteristics. CDKN2B-AS1 attenuation or miR-141 overexpression decreased CCND1/CCND2 expression, resulting in reduced RAC1/pPXN that are involved in migration, invasion and epithelial–mesenchymal transition. This study, for the first time, deciphered the role of CDKN2B-AS1 /miR-141/Cyclin D axis in RCC and highlights this network as a promising therapeutic target for the regulation of EMT driven metastasis in RCC.

Background/Aims: The long noncoding RNA homeobox (HOX) transcript antisense intergenic RNA (HOTAIR) has been demonstrated to be a vital modulator in the proliferation and metastasis of ovarian cancer cells, but its potential molecular mechanism remains to be elucidated. In the current study, we aimed to uncover the biological role of lncRNA HOTAIR and its underlying regulatory mechanism in the progression and metastasis of ovarian cancer. Methods: HOTAIR expression was detected by quantitative RT-PCR (qRT-PCR) and northern blotting. The SKOV3 ovarian cancer cell line was chosen for the subsequent assays. In addition, the molecular mRNA and protein expression levels were examined by qRT-PCR and western blotting. The competitive endogenous RNA (ceRNA) mechanism was validated by bioinformatics analysis and a dual luciferase reporter gene assay. Results: HOTAIR expression was significantly higher in ovarian carcinoma tissues and cell lines than in the control counterparts. Both CCND1 and CCND2 were downstream targets of miR-206. The inhibition of HOTAIR elevated the expression of miR-206 and inhibited the expression of CCND1 and CCND2. Moreover, CCND1 and CCND2 were highly expressed in ovarian cancer tissues, and their expression was positively correlated with HOTAIR expression. Finally, the functional assays indicated that the anticancer effects of miR-206 could be rescued by the simultaneous overexpression of either CCND1 or CCND2 in ovarian cancer. Conclusion: HOTAIR enhanced CCND1 and CCND2 expression by negatively modulating miR-206 expression and stimulating the proliferation, cell cycle progression, migration and invasion of ovarian cancer cells.

Diabetic cardiomyopathy (DbCM) is responsible for increased morbidity and mortality in patients with diabetes and heart failure. However, the pathogenesis of DbCM has not yet been identified. Here, we investigated the important role of lncRNA‐ZFAS1 in the pathological process of DbCM, which is associated with ferroptosis. Microarray data analysis of DbCM in patients or mouse models from GEO revealed the significance of ZFAS1 and the significant downregulation of miR‐150‐5p and CCND2. Briefly, DbCM was established in high glucose (HG)–treated cardiomyocytes and db/db mice to form in vitro and in vivo models. Ad‐ZFAS1, Ad‐sh‐ZFAS1, mimic miR‐150‐5p, Ad‐CCND2 and Ad‐sh‐CCND2 were intracoronarily administered to the mouse model or transfected into HG‐treated cardiomyocytes to determine whether ZFAS1 regulates miR‐150‐5p and CCND2 in ferroptosis. The effect of ZFAS1 on the left ventricular myocardial tissues of db/db mice and HG‐treated cardiomyocytes, ferroptosis and apoptosis was determined by Masson staining, immunohistochemical staining, Western blotting, monobromobimane staining, immunofluorescence staining and JC‐1 staining. The relationships among ZFAS1, miR‐150‐5p and CCND2 were evaluated using dual‐luciferase reporter assays and RNA pull‐down assays. Inhibition of ZFAS1 led to reduced collagen deposition, decreased cardiomyocyte apoptosis and ferroptosis, and attenuated DbCM progression. ZFAS1 sponges miR‐150‐5p to downregulate CCND2 expression. Ad‐sh‐ZFAS1, miR‐150‐5p mimic, and Ad‐CCND2 transfection attenuated ferroptosis and DbCM development both in vitro and in vivo. However, transfection with Ad‐ZFAS1 could reverse the positive effects of miR‐150‐5p mimic and Ad‐CCND2 in vitro and in vivo. lncRNA‐ZFAS1 acted as a ceRNA to sponge miR‐150‐5p and downregulate CCND2 to promote cardiomyocyte ferroptosis and DbCM development. Thus, ZFAS1 inhibition could be a promising therapeutic target for the treatment and prevention of DbCM.

Regeneration and homeostatic turnover of solid tissues depend on the proliferation of symmetrically dividing adult stem cells, which either remain stem cells or differentiate based on their niche position. Here we demonstrate that in zebrafish lateral line sensory organs, stem and progenitor cell proliferation are independently regulated by two cyclinD genes. Loss of ccnd2a impairs stem cell proliferation during development, while loss of ccndx disrupts hair cell progenitor proliferation but allows normal differentiation. Notably, ccnd2a can functionally replace ccndx , indicating that the respective effects of these Cyclins on proliferation are due to cell type-specific expression. However, even though hair cell progenitors differentiate normally in ccndx mutants, they are mispolarized due to hes2 and Emx2 downregulation. Thus, regulated proliferation ensures that equal numbers of hair cells are polarized in opposite directions. Our study reveals cell type-specific roles for cyclinD genes in regulating the different populations of symmetrically dividing cells governing organ development and regeneration, with implications for regenerative medicine and disease. Proliferation of adult tissue stem cells is tightly regulated to balance maintenance of the tissue against stem cell exhaustion or cancerous expansion. Here they show that zebrafish lateral line progenitors are differentially regulated by two cyclinD genes, which control developmental and adult progenitor proliferation as well as hair cell polarization.

MicroRNAs play crucial roles in various types of diseases. However, to date, no information about the role of miR-497 in the development of atherosclerosis has been reported. This study investigated the possible role of miR-497 in vascular endothelial cell injury during the early stage of atherosclerosis. The expression level of miR-497 in human umbilical vein endothelial cells (HUVECs) exposed to ox-LDL was detected using qRT-PCR. To perform gain of function and loss of function analyses, miR-497 mimics were transfected into HUVECs, and miR-497 inhibitors were transfected into HUVECs stimulated with ox-LDL. Flow cytometry was used to analyze cell cycle progression and apoptosis. EdU and CCK-8 assays were employed to detect DNA synthesis and cell proliferation, respectively. After bioinformatics prediction, a dual Luciferase Reporter assay was used to analyze the direct target genes of miR-497. The mRNA and protein levels of the target genes were detected using qRT-PCR and western blot analyses, respectively. Caspase-9/3 activity was analyzed to determine the mechanism of endothelial dysfunction. We showed that miR-497 was significantly upregulated in HUVECs stimulated with ox-LDL. Ectopic expression of miR-497 suppressed cell proliferation, induced apoptosis and increased the activity of caspase-9/3. After verification, Bcl2 and CCND2 were shown to be direct target genes of miR-497 in HUVECs. MiR-497 significantly suppressed cell proliferation by arresting the cell cycle through the CCND2 protein and induced apoptosis through the Bcl2/Bax-caspase9-caspase3 pathway. Overall, our study shows that miR-497 might play a role in the development of atherosclerosis by inducing apoptosis and suppressing the proliferation of vascular endothelial cells. Therefore, miR-497 could be a potential therapeutic target for the treatment of atherosclerosis.

Unnur Thorsteinsdottir, Kari Stefansson and colleagues identify low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. The newly discovered variants include an intronic variant associated with altered expression of CCND2 , two independent missense variants in PAM and a rare frameshift variant in PDX1 . Through whole-genome sequencing of 2,630 Icelanders and imputation into 11,114 Icelandic cases and 267,140 controls followed by testing in Danish and Iranian samples, we discovered 4 previously unreported variants affecting risk of type 2 diabetes (T2D). A low-frequency (1.47%) variant in intron 1 of CCND2 , rs76895963[G], reduces risk of T2D by half (odds ratio (OR) = 0.53, P = 5.0 × 10 −21 ) and is correlated with increased CCND2 expression. Notably, this variant is also associated with both greater height and higher body mass index (1.17 cm per allele, P = 5.5 × 10 −12 and 0.56 kg/m 2 per allele, P = 6.5 × 10 −7 , respectively). In addition, two missense variants in PAM , encoding p.Asp563Gly (frequency of 4.98%) and p.Ser539Trp (frequency of 0.65%), confer moderately higher risk of T2D (OR = 1.23, P = 3.9 × 10 −10 and OR = 1.47, P = 1.7 × 10 −5 , respectively), and a rare (0.20%) frameshift variant in PDX1 , encoding p.Gly218Alafs*12, associates with high risk of T2D (OR = 2.27, P = 7.3 × 10 −7 ).

Cells derived from the amniotic foetal membrane of human term placenta have drawn particular attention mainly for their plasticity and immunological properties, which render them interesting for stem‐cell research and cell‐based therapeutic applications. In particular, we have previously demonstrated that amniotic mesenchymal tissue cells (AMTC) inhibit lymphocyte proliferation in vitro and suppress the generation and maturation of monocyte‐derived dendritic cells. Here, we show that AMTC also significantly reduce the proliferation of cancer cell lines of haematopoietic and non‐haematopoietic origin, in both cell–cell contact and transwell co‐cultures, therefore suggesting the involvement of yet‐unknown inhibitory soluble factor(s) in this ‘cell growth restraint’. Importantly, we provide evidence that the anti‐proliferative effect of AMTC is associated with induction of cell cycle arrest in G0/G1 phase. Gene expression analyses demonstrate that AMTC can down‐regulate cancer cells' mRNA expression of genes associated with cell cycle progression, such as cyclins (cyclin D2, cyclin E1, cyclin H) and cyclin‐dependent kinase (CDK4, CDK6 and CDK2), whilst they up‐regulate cell cycle negative regulator such as p15 and p21, consistent with a block in G0/G1 phase with no progression to S phase. Taken together, these findings warrant further studies to investigate the applicability of these cells for controlling cancer cell proliferation in vivo.

Rational control of rodent populations is crucial for maintaining ecosystem balance and mitigating agricultural economic losses. Follicle development plays a pivotal role in determining animal population abundance, and photoperiod serves as the primary environmental cue affecting this process. Investigating the mechanisms through which photoperiod influences follicle development in the striped hamster (Cricetulus barabensis) offers a promising molecular target for the effective and sustainable management of rodent populations. This study employed hematoxylin and eosin (HE) staining to evaluate ovarian developmental status under different photoperiods, including quantification of follicles at various developmental stages and the number and thickness of granulosa cell layer, thereby elucidating the effects of photoperiod on follicle development. Subsequently, enzyme-linked immunosorbent assay (ELISA) was used to measure serum FSH and fecal E2 concentrations, while real-time quantitative PCR was performed to determine mRNA levels of CCND1 and CCND2. Correlation analyses between these markers and follicle counts were conducted to identify key factors involved in follicle development. Furthermore, both real-time quantitative PCR and Western blotting were utilized to investigate the expression of transcription factors FOXO1, FOXL2, and NR5A2 in the ovary at the mRNA and protein levels, respectively, and their relationships with follicle numbers were analyzed, to reveal the potential molecular pathways through which photoperiod regulates follicle development in the striped hamster. The results demonstrate that LP enhances the synthesis of FSH, promotes granulosa cell proliferation, and stimulates follicle development, whereas SP exerts an opposing effect in the striped hamster. FSH is a key hormone involved in follicle development regulated by photoperiods, and CCND2 influences follicle development by modulating granulosa cell proliferation. Additionally, photoperiod alters the expression levels of transcription factors FOXO1, FOXL2, and NR5A2. Correlation analyses revealed that serum FSH concentration was significantly positively correlated with the expression levels of FOXO1 and FOXL2. In turn, the expression of FOXO1 and FOXL2 was significantly positively associated with that of NR5A2, which also showed a significant positive correlation with CCND2 expression. These results suggest a potential regulatory pathway-FSH-FOX-NR5A2-CCND2-involved in photoperiod-dependent follicle development in the striped hamster. The FSH-FOX-NR5A2-CCND2 pathway represents a potential molecular mechanism by which photoperiod regulates follicle development, supported by robust correlative evidence in the striped hamster. The transcription factors FOXO1, FOXL2, and NR5A2 are identified as candidate targets of reproductive activity, with NR5A2 showing a stronger correlation than FOXO1 and FOXL2, thus providing a theoretical foundation for the rational control of rodent population dynamics.

Wei Zheng and colleagues report genome-wide analyses in east Asians and identify three new loci associated with colorectal cancer risk. To identify new genetic factors for colorectal cancer (CRC), we conducted a genome-wide association study in east Asians. By analyzing genome-wide data in 2,098 cases and 5,749 controls, we selected 64 promising SNPs for replication in an independent set of samples, including up to 5,358 cases and 5,922 controls. We identified four SNPs with association P values of 8.58 × 10 −7 to 3.77 × 10 −10 in the combined analysis of all east Asian samples. Three of the four were replicated in a study conducted in 26,060 individuals of European descent, with combined P values of 1.22 × 10 −10 for rs647161 (5q31.1), 6.64 × 10 −9 for rs2423279 (20p12.3) and 3.06 × 10 −8 for rs10774214 (12p13.32 near the CCND2 gene), derived from meta-analysis of data from both east Asian and European-ancestry populations. This study identified three new CRC susceptibility loci and provides additional insight into the genetics and biology of CRC.