JMJD2A mediates transcriptional activation of SFRP4 and regulates oxidative stress and mitochondrial dysfunction in heart failure.

The importance of mitochondrial dysfunction and oxidative stress has been indicated in the progression of heart failure (HF). The molecular mechanisms, however, remain to be fully elucidated. This study aimed to explore the role and underlying mechanism of secreted frizzled-related protein 4 (SFRP4) in these two events in HF. Mice with HF were developed using transverse aortic constriction, and hematoxylin-eosin staining, MASSON staining, and Terminal deoxynucleotidyl transferase (TdT)-mediated 2'-Deoxyuridine 5'- Triphosphate nick end labeling (TUNEL assays) were conducted to detect morphological damage in the myocardial tissues of mice. HL-1 mouse cardiomyocytes were induced with isoproterenol (ISO), and cell viability and apoptosis were examined using cell counting kit-8 and TUNEL assays. SFRP4 and Jumonji domain-containing protein 2A (JMJD2A) were highly expressed in myocardial tissues. Suppression of SFRP4 alleviated apoptosis and fibrosis in myocardial tissues of mice. In addition, the extent of mitochondrial dysfunction and oxidative stress in damaged myocardial tissues and HL-1 cells was mitigated by SFRP4 inhibition as well. JMJD2A catalyzed demethylation modification of the SFRP4 promoter, thus promoting SFRP4 transcription in the development of HF. JMJD2A is responsible for SFRP4 transcription activation in the failing hearts of mice. Blockade of JMJD2A or SFRP4 might be a novel therapy effective in mitigating HF progression.

A Five-gene Signature based on MicroRNA for Predicting Prognosis and Immunotherapy in Stomach Adenocarcinoma.

AIMS: We aimed to classify molecular subtypes and establish a prognostic gene signature based on miRNAs for the prognostic prediction and therapeutic response in Stomach adenocarcinoma (STAD). BACKGROUND: STAD is a common diagnosed gastrointestinal malignancy and its heterogeneity is a big challenge that influences prognosis and precision therapies. Present study was designed to classify molecular subtypes and construct a prognostic gene signature based on miRNAs for the prognostic prediction and therapeutic response in STAD. OBJECTIVE: The objective of this study is to investigate the molecular subtypes and prognostic model for STAD. METHODS: A STAD specific miRNA-messenger RNA (mRNA) competing endogenous RNA (ceRNA) network was generated using the RNA-Seq and miRNA expression profiles from The Cancer Genome Atlas (TCGA) database, in which miRNA-related mRNAs were screened. Molecular subtypes were then determined using miRNA-related genes. Through univariate Cox analysis and multivariate regression analysis, a prognostic model was established in GSE84437 Train dataset and validated in GSE84437 Test, TCGA, GSE84437 and GSE66229 datasets. Immunotherapy datasets were employed for assessing the performance of the risk model. Finally, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was applied to validate the expression of hub genes used for the risk score signature. RESULTS: We constructed a ceRNA network containing 84 miRNAs and 907 mRNAs and determined two molecular subtypes based on 26 genes from the intersection of TCGASTAD and GSE84437 datasets. Subtype S2 had poor prognosis, lower tumor mutational burden, higher immune score and lower response to immunotherapy. Subtype S1 was more sensitive to Sorafenib, Pyrimethamine, Salubrinal, Gemcitabine, Vinorelbine and AKT inhibitor VIII. Next, a five-gene signature was generated and its robustness was validated in Test and external datasets. This risk model also had a good prediction performance in immunotherapy datasets. CONCLUSION: This study promotes the underlying mechanisms of miRNA-based genes in STAD and offers directions for classification. A five-gene signature accurately predicts the prognosis and helps therapeutic options.

The KMT1A/TIMP3/PI3K/AKT circuit regulates tumor growth in cervical cancer.

The epigenetic mechanism of tissue inhibitor of metalloproteinase 3 (TIMP3), a well-known tumor suppressor, in cervical cancer (CC) is still unclear. Integrated GEO database, protein interaction network, and a pan-cancer analysis revealed a KMT1A/TIMP3 axis in CC. KMT1A was highly expressed, and TIMP3 was poorly expressed in CC tissues and cells. KMT1A inhibited the activity of TIMP3. Silencing of KMT1A hampered the proliferation, migration, invasion, tumorigenesis and metastases of CC cells in vivo, and increased the apoptosis of cells. TIMP3 downregulation promoted the malignant phenotype and in vivo tumorigenesis and metastasis of CC cells. KMT1A downregulation impaired PI3K/AKT pathway in cells, while TIMP3 silencing promoted PI3K/AKT pathway activity. We propose a novel perspective that KMT1A involves in the growth and metastases via the TIMP3/PI3K/AKT axis in CC. In summary, our study identified a vital role played by KMT1A in the development of CC and the epigenetic mechanism, indicating that targeting KMT1A-related pathways could be conducive to the therapies for CC.

Analysis of miR-148b expression differences in stage-I and II parosteal osteosarcoma.

Expression of human serum albumin-micro RNA miR-148b in patients with stage-I and II parosteal osteosarcoma and its effect on prognosis were investigated. A total of 47 cases of fresh tissues of stage-I and II parosteal osteosarcoma and the corresponding para-carcinoma normal bone tissues resected by operation were collected; the expression of miR-148b in parosteal osteosarcoma tissues and normal bone tissues was detected, and the correlations of miR-148b expression in parosteal osteosarcoma tissues with clinicopathological parameters and prognosis were analyzed. The expression level of miR-148b in parosteal osteosarcoma tissues was significantly lower than that in para-carcinoma normal tissues (P<0.05). It was found that the low expression of miR-148b was correlated with the lung metastasis (P<0.05). Moreover, Kaplan-Meier survival curve analysis showed that the overall survival rate of patients in the low-expression miR-148b group was lower than that in the high-expression group (P<0.05). Multivariate Cox regression analysis revealed that the miR-148b level (P=0.003) was an independent prognostic factor affecting the prognosis. The results of this study showed that the expression of miR-148b in stage-I and II parosteal osteosarcoma tissues declines, which is related to the poor clinical prognosis of parosteal osteosarcoma.