Journal of Cellular and Molecular Medicine最新文献

In Y Chen et al¹, the published article contains errors in Figure 2G. The corrected Figure 2G is below. The authors confirmed that the conclusion of this article remain unchanged.

In Hu et al.,¹ the published article contains errors in Figure 4E,F. The figure of group inhibitor + PBS in Figure 4E was mis-uploaded. The corrected Figure 4 is below. The authors confirmed that all results and conclusions of this article remain unchanged.

Metastasis is the primary cause of death of hepatocellular carcinoma (HCC), while the mechanism underlying this severe disease remains largely unclear. The Kruppel-like factor (KLF) family is one of the largest transcription factor families that control multiple physiologic and pathologic processes by governing the cellular transcriptome. To identify metastatic regulators of HCC, we conducted gene expression profiling on the MHCC97 cell series, a set of subclones of the original MHCC97 that was established by in vivo metastasis selection therefore harbouring differential metastatic capacities. We found that the expression of KLF9, a member of the KLF family, was dramatically repressed in the metastatic progeny clone of the MHCC97 cells. Functional studies revealed overexpression of KLF9 suppressed HCC migration in vitro and metastasis in vivo, while knockdown of KLF9 was sufficient to promote cell migration and metastasis accordingly. Mechanistically, we found the expression of KLF9 can reverse the pro-metastatic epithelial-mesenchymal transition (EMT) program via direct binding to the promoter regions of essential mesenchymal genes, thus repressing their expression. Interestingly, we further revealed that KLF9 was, in turn, directly suppressed by a mesenchymal transcription factor Slug, suggesting an intriguing negative feedback loop between KLF9 and the EMT program. Using clinical samples, we found that KLF9 was not only downregulated in HCC tissue compared to its normal counterparts but also further reduced in the HCC samples of whom had developed metastatic lesions. Together, we established a critical transcription factor that represses HCC metastasis, which is clinically and mechanically significant in HCC therapies.

Shortened foetal femur length (FL) is a common abnormal phenotype that often causes anxiety in pregnant women, and standard clinical treatments remain unavailable. We investigated the clinical characteristics, genetic aetiology and obstetric pregnancy outcomes of foetuses with short FL and provided a reference for perinatal management of such cases. Chromosomal microarray analysis was used to analyse the copy number variations (CNV) in short FL foetuses. Of the 218 foetuses with short FL, 33 foetuses exhibited abnormal CNVs, including 19 with pathogenic CNVs and 14 with variations of uncertain clinical significance. Of the 19 foetuses with pathogenic CNVs, four had aneuploidy, 14 had deletions/duplications, and one had pathogenic uniparental diploidy. The 7q11.23 microdeletion was detected in three foetuses. The severity of short FL was not associated with the rate of pathogenic CNVs. The duration of short FL for the intrauterine ultrasound phenotype in foetuses carrying a pathogenic CNV was independent of the gestational age. Further, maternal age was not associated with the incidence of foetal pathogenic CNVs. Adverse pregnancy outcomes occurred in 77 cases, including termination of pregnancy in 63 cases, postnatal dwarfed foetuses with intellectual disability in 11 cases, and three deaths within 3 months of birth. Pathogenic CNVs closely related to foetal short FL were identified, among which the 7q11.23 microdeletion was highly associated with short FL development. This study provides a reference for the perinatal management of foetuses with short FL.

To explore the underlying mechanism of lncRNA MALAT1 in the pathogenesis of diabetic cardiomyopathy (DCM). DCM models were confirmed in db/db mice. MiRNAs in myocardium were detected by miRNA sequencing. The interactions of miR-185-5p with MALAT1 and RhoA were validated by dual-luciferase reporter assays. Primary neonatal cardiomyocytes were cultured with 5.5 or 30 mmol/L D-glucose (HG) in the presence or absence of MALAT1-shRNA and fasudil, a ROCK inhibitor. MALAT1 and miR-185-5p expression were determined by real-time quantitative PCR. The apoptotic cardiomyocytes were evaluated using flow cytometry and TUNEL staining. SOD activity and MDA contents were measured. The ROCK activity, phosphorylation of Drp1^S616, mitofusin 2 and apoptosis-related proteins were analysed by Western blotting. Mitochondrial membrane potential was examined by JC-1. MALAT1 was significantly up-regulated while miR-185-5p was down-regulated in myocardium of db/db mice and HG-induced cardiomyocytes. MALAT1 regulated RhoA/ROCK pathway via sponging miR-185-5p in cardiomyocytes in HG. Knockdown of MALAT1 and fasudil all inhibited HG-induced oxidative stress, and alleviated imbalance of mitochondrial dynamics and mitochondrial dysfunction, accompanied by reduced cardiomyocyte apoptosis. MALAT1 activated the RhoA/ROCK pathway via sponging miR-185-5p and mediated HG-induced oxidative stress, mitochondrial damage and apoptosis of cardiomyocytes in mice.

In Chi et al.,¹ the published article contains errors in Figures 3 and 8. The bar-graph (Figure 3F) was accidentally misused as Figure 3G. The immunofluorescence picture of the control group (Figure 2G) was accidentally misused in shHOTAIR group (Figure 8B). The corrected figures and their legends are shown below. The authors confirmed all results and conclusions of this article remain unchanged.

GP-2250, a novel anticancer agent, severely limits the energy metabolism, as demonstrated by the inhibition of hexokinase 2 and glyceraldehyde-3-phosphate dehydrogenase and a decrease of ATP. Rescue experiments with supplementary pyruvate or oxaloacetate demonstrated that a TCA cycle deficit largely contributed to cytotoxicity. Activation of the energy-deficit sensor, AMP-dependent protein kinase, was associated with increased phosphorylation of acetyl-CoA carboxylase and Raptor, pointing to a possible deficit in the synthesis of fatty acids and proteins as essential cell components. Binding of p65 to DNA was dose-dependently reduced in nuclear lysates. A transcriptional deficit of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) was substantiated by the downregulation of cyclin D1 and of the anti-apoptotic Bcl2, in line with reduction in tumour cell proliferation and induction of apoptosis, respectively. The upregulation of p53 concomitant with an excess of ROS supported apoptosis. Thus, the anticancer activity of GP-2250 is a result of disruption of energy metabolism and inhibition of tumour promotion by NF-κB.

The locus at 17q12 erb-b2 receptor tyrosine kinase 2 (ERBB2) has been heavily amplificated and overexpressed in gastric cancer (GC), but it remains to be elucidated about the clinical significance of the co-amplification and co-overexpression of PGAP3 gene located around ERBB2 in GC. The profile of PGAP3 and ERBB2 in four GC cell lines and tissue microarrays containing 418 primary GC tissues was assessed to investigate the co-overexpression and clinical significance of the co-amplified genes, and to evaluate the impact of the co-amplified genes on the malignancy of GC. Co-amplification of PGAP3 and ERBB2 accompanied with co-overexpression was observed in a haploid chromosome 17 of NCI-N87 cells with double minutes (DMs). PGAP3 and ERBB2 were overexpressed and positively correlated in 418 GC patients. Co-overexpression of the PGAP3 and ERBB2 was correlated with T stage, TNM stage, tumour size, intestinal histological type and poor survival proportion in 141 GC patients. In vitro, knockdown of the endogenous PGAP3 or ERBB2 decreased cell proliferation and invasion, increased G1 phase accumulation and induced apoptosis in NCI-N87 cells. Furthermore, combined silencing of PGAP3 and ERBB2 showed an additive effect on resisting proliferation of NCI-N87 cells compared with targeting ERBB2 or PGAP3 alone. Taken together, the co-overexpression of PGAP3 and ERBB2 may be crucial due to its significant correlation with clinicopathological factors of GC. Haploid gain of PGAP3 co-amplified with ERBB2 is sufficient to facilitate the malignancy and progression of GC cells in a synergistic way.

Endometrial cancer (EC) is one of the most common gynaecological malignant tumours with a high incidence, leading to urgent demands for exploring novel carcinogenic mechanisms and developing rational therapeutic strategies. The rac family of small GTPase 3 (RAC3) functions as an oncogene in various human malignant tumours and plays an important role in tumour development. However, the critical roles of RAC3 in the progression of EC need further investigation. Based on TCGA, single-cell RNA-Seq, CCLE and clinical specimens, we revealed that the RAC3 was specifically distributed in EC tumour cells compared to normal tissues and functioned as an independent diagnostic marker with a high area under curve (AUC) score. Meanwhile, the RAC3 expression in EC tissues was also correlated with a poor prognosis. In detail, the high levels of RAC3 in EC tissues were reversely associated with CD8⁺T cell infiltration and orchestrated an immunosuppressive microenvironment. Furthermore, RAC3 accelerated tumour cell proliferation and inhibited its apoptosis, without impacting cell cycle stages. Importantly, silencing RAC3 improved the sensitivity of EC cells to chemotherapeutic drugs. In this paper, we revealed that RAC3 was predominantly expressed in EC and significantly correlated with the progression of EC via inducing immunosuppression and regulating tumour cell viability, providing a novel diagnostic biomarker and a promising strategy for sensitizing chemotherapy to EC.

Sulfur mustard (SM) is a blister-producing chemical warfare agent which could lead to a cascade of systemic damage, especially severe acute lung injury. Oxidative stress is considered to be vital processes for the SM toxicity mechanism. We previously proved the therapeutic effect of exosomes derived from bone marrow mesenchymal stromal cells in promoting the repair of alveolar epithelial barrier and inhibiting apoptosis. However, the key functional components in exosomes and the underlying mechanisms have not been fully elaborated. This research shed light on the function of the key components of human umbilical cord mesenchymal stem cell-derived exosomes (HMSCs-Ex). We noted that HMSCs-Ex-derived miR-199a-5p played a vital role in reducing pneumonocyte oxidative stress and apoptosis by reducing reactive oxygen species, lipid peroxidation products and increasing the activities of antioxidant enzymes in BEAS-2B cells and mouse models after exposure to SM for 24 h. Furthermore, we demonstrated that the overexpression of miR-199a-5p in HMSCs-Ex treatment induced a further decrease of Caveolin1 and the activation of the mRNA and protein level of NRF2, HO1 and NQO1, compared with HMSCs-Ex administration. In summary, miR-199a-5p was one of the key molecules in HMSCs-Ex that attenuated SM-associated oxidative stress via regulating CAV1/NRF2 signalling pathway.