Screening for metastasis-related genes in mouse melanoma cells through sequential tail vein injection.

Tumor metastasis, responsible for approximately 90% of cancer-associated mortality, remains poorly understood. Here in this study, we employed a melanoma lung metastasis model to screen for metastasis-related genes. By sequential tail vein injection of mouse melanoma B16F10 cells and the subsequently derived cells from lung metastasis into BALB/c mice, we successfully obtained highly metastatic B16F15 cells after five rounds of in vivo screening. RNA-sequencing analysis of B16F15 and B16F10 cells revealed a number of differentially expressed genes, some of these genes have previously been associated with tumor metastasis while others are novel discoveries. The identification of these metastasis-related genes not only improves our understanding of the metastasis mechanisms, but also provides potential diagnostic biomarkers and therapeutic targets for metastatic melanoma.

Deciphering the chromatin spatial organization landscapes during BMMSC differentiation.

The differentiation imbalance in bone marrow mesenchymal stem cells (BMMSCs) is critical for the development of bone density diseases as the population ages. BMMSCs are precursor cells for osteoblasts and adipocytes; however, the chromatin organization landscapes during BMMSC differentiation remain elusive. In this study, we systematically delineate the four-dimensional genome and dynamic epigenetic atlas of BMMSCs by RNA sequencing, assay for transposase-accessible chromatin sequencing, and high-throughput chromosome conformation capture. The structure analyses reveal 17.5% common and 28.5%-30% specific loops among BMMSCs, osteoblasts, and adipocytes. The subsequent correlation of genome-wide association studies and expression quantitative trait locus (eQTL) data with multi-omics analysis reveal 274 genes and 3634 single nucleotide polymorphisms (SNPs) associated with bone degeneration and osteoporosis (OP). We hypothesize that SNP mutations affect transcription factor (TF) binding sites, thereby affecting changes in gene expression. Furthermore, 26 motifs, 260 TFs, and 291 SNPs are identified to affect the eQTL. Among these genes, DAAM2, TIMP2, and TMEM241 are found to be essential for diseases such as bone degeneration and OP and may serve as potential drug targets.

A pooled analysis of the association between sarcopenia and osteoporosis.

BACKGROUND: Sarcopenia is a progressive generalized skeletal muscle disorder that causes the accelerated loss of muscle mass and function. Osteoporosis is a systemic condition of the skeleton that results in low bone mass and quality. Several studies have suggested that osteoporosis and sarcopenia are interrelated; however, a few studies indicate the lack of a significant association between sarcopenia and osteoporosis. We aimed to evaluate the association between sarcopenia and osteoporosis via a systematic review and pooled analysis. METHODS: From the inception of the PubMed and Embase databases until September 2022, we conducted a systematic search for studies evaluating the relationship between sarcopenia and osteoporosis. Study appraisal and synthesis methods: We included observational studies that provided 95% confidence intervals (CIs) and risk estimates. Two reviewers independently extracted data and assessed the quality of the research. The random-effects model was applied to the pool analysis, and the odds ratios (ORs) and 95% CIs were finally calculated. RESULTS: The primary statistic was the mutual risk between sarcopenia and osteoporosis. According to the inclusion criteria, 56 studies (796,914 participants) were finally included. Sarcopenia was significantly correlative to the risk of osteoporosis (OR, 3.06; 95% CI, 2.30-4.08), and each standard deviation increase in relative appendicular skeletal muscle mass was significantly related to a decreased risk of osteoporosis (OR, 0.65; 95% CI, 0.56-0.75). Osteoporosis observably referred to a higher risk of sarcopenia (OR, 2.63; 95% CI, 1.98-3.49). CONCLUSION: Our research indicated that sarcopenia and osteoporosis are highly positively correlated. Osteoporosis is closely associated with the risk of sarcopenia. Our finding highlights the importance of sarcopenia screening for those at risk of osteoporosis, and vice versa. However, heterogeneity was noted among the studies, and this might have influenced the accuracy of the results. Therefore, the results of our study should be interpreted with caution.

Progress on the role and mechanism of MT1-MMP in tumor metastasis.

The matrix metallopeptidase family (matrix metallopeptidase, MMPs) is a class of zinc-dependent endopeptidases that can degrade most extracellular matrices. MT1-MMP (membrane type 1 metalloprotease) is an important metallopeptidase, which is located on plasma membrane and highly expressed in most tumors. MT1-MMP promotes cancer metastasis through affecting the extracellular matrix remodeling, angiogenesis, lipid metabolism, and inflammation. However, the mechanisms of MT1-MMP in different tumors have not been fully elucidated. In this review, we summarize the latest progress and the metastasis-promoting regulatory mechanisms of MT1-MMP in different tumors, which will provide references for its in-depth research and application in the field of cancer biology.

Caenorhabditis elegans NHR-14/HNF4α regulates DNA damage-induced apoptosis through cooperating with cep-1/p53.

BACKGROUND: Nuclear hormone receptors are involved in transcriptional regulation and many important cellular processes including development and metabolism. However, its role in DNA damage-induced apoptosis remains elusive. METHODS: Synchronized young adult animals were irradiated with different doses of gamma-Ray, and then put back to culture at 20 °C. Germline cell apoptosis was scored at different time point. RESULTS: Deletion of nhr-14 led to decreased DNA damage-induced germline apoptosis, but not the physiological programmed cell death. We also demonstrate that nhr-14 functions downstream of the DNA damage checkpoint pathway. Moreover, we show that nhr-14 regulates egl-1 and ced-13 transcription upon DNA damage. Mechanistically, NHR-14 forms a complex with CEP-1/p53 and binds directly to the egl-1 promoter to promote egl-1 transcription.. CONCLUSIONS: Our results indicate that NHR-14/HNF4α cooperates with CEP-1/p53 to regulate DNA damage-induced apoptosis. Video abstract.

The prognosis biomarkers based on m6A-related lncRNAs for myeloid leukemia patients.

BACKGROUND: Chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) are two common malignant disorders in leukemia. Although potent drugs are emerging, CML and AML may still relapse after the drug treatment is stopped. N6-methyladenosine (m6A) and lncRNAs play certain roles in the occurrence and development of tumors, but m6A-modified LncRNAs in ML remain to be further investigated. METHODS: In this study, we extracted and analyzed the TCGA gene expression profile of 151 ML patients and the clinical data. On this basis, we then evaluated the immune infiltration capacity of ML and LASSO-penalized Cox analysis was applied to construct the prognostic model based on m6A related lncRNAs to verify the prognostic risk in clinical features of ML. Quantitative reverse transcription PCR was used to detect the expression level of LncRNA in in ML cell lines K562, MOLM13 and acute monocytic leukemia cell line THP-1. RESULTS: We found 70 m6A-related lncRNAs that were related to prognosis, and speculated that the content of stromal cells and immune cells would correlate with the survival of patients with ML. Next, Prognostic risk model of m6A-related lncRNAs was validated to have excellent consistency in clinical features of ML. Finally, we verified the expression levels of CRNDE, CHROMR and NARF-IT1 in ML cell lines K562, MOLM13 and acute monocytic leukemia cell line THP-1, which were significant. CONCLUSIONS: The research provides clues for the prognosis prediction of ML patients by using the m6A-related lncRNAs model we have created, and clarifies the accuracy and authenticity of it.

Long non-coding RNA taurine upregulated gene 1 is downregulated in osteoporosis and influences the osteogenic differentiation of bone marrow mesenchymal stem cells.

BACKGROUND: With aging, an imbalance in bone remodeling leading to increased bone resorption and decreased bone formation is thought to contribute to osteoporosis. Osteoblastic differentiation of bone marrow mesenchymal stem cells (BMMSCs) plays a vital role in the pathogenesis of osteoporosis. However, the detailed molecular mechanisms of osteoporosis remain incompletely understood. Given that long non-coding RNA taurine upregulated gene 1 (lnc TUG1) plays a critical role in the osteogenic differentiation, and microRNA-23b (miR-23b) as a putative sponge for lnc TUG1 has upregulated expression in osteoporosis. Therefore, this study investigated the roles of TUG1/miR-23b in osteoporotic pathology. MATERIAL AND METHODS: TUG1 and miR-23b expression in the plasma of osteoporotic patients were evaluated by quantitative real-time PCR (qRT-PCR). The osteogenic differentiation in human BMMSCs was evaluated by qRT-PCR, western blot, Alizarin red staining after knockdown of TUG1 by small interfering RNA (siRNA) treatment. RESULTS: Decreased expression of TUG1 and increased expression of miR-23b evident in the plasma of patients with osteoporosis than in that of age- and sex-matched healthy controls. Additionally, increased miR-23b expression inhibited runt-related transcription factor 2 (RUNX2), osteocalcin, and osteopontin expression and reduced calcified nodule formation based on the results of qRT-PCR, western blot, and Alizarin Red S staining. CONCLUSION: The study for the first time reported that silence of lncRNA TUG1 significantly suppressed the osteogenic differentiation of BMMSCs possibly by targeting the miR-23b/RUNX2 signaling pathway. This mechanism of TUG1/miR-23b/RUNX2 signaling within the osteogenic differentiation of BMMSCs might provide new insight for the development of lncRNA-directed diagnostic and therapeutic strategies for osteoporosis.

The T296V Mutant of Amorpha-4,11-diene Synthase Is Defective in Allylic Diphosphate Isomerization but Retains the Ability To Cyclize the Intermediate (3R)-Nerolidyl Diphosphate to Amorpha-4,11-diene.

The T296V mutant of amorpha-4,11-diene synthase catalyzes the abortive conversion of the natural substrate (E,E)-farnesyl diphosphate mainly into the acyclic product (E)-ß-farnesene (88%) instead of the natural bicyclic sesquiterpene amorphadiene (7%). Incubation of the T296V mutant with (3R,6E)-nerolidyl diphosphate resulted in cyclization to amorphadiene. Analysis of additional mutants of amino acid residue 296 and in vitro assays with the intermediate analogue (2Z,6E)-farnesyl diphosphate as well as (3S,6E)-nerolidyl diphosphate demonstrated that the T296V mutant can no longer catalyze the allylic rearrangement of farnesyl diphosphate to the normal intermediate (3R,6E)-nerolidyl diphosphate, while retaining the ability to cyclize (3R,6E)-nerolidyl diphosphate to amorphadiene. The T296A mutant predominantly retained amorphadiene synthase activity, indicating that neither the hydroxyl nor the methyl group of the Thr296 side chain is required for cyclase activity.