Identification of Key lncRNAs Associated with Immune Infiltration and Prognosis in Gastric Cancer.

Long non-coding RNAs (lncRNAs), as promising novel biomarkers for cancer treatment and prognosis, can function as tumor suppressors and oncogenes in the occurrence and development of many types of cancer, including gastric cancer (GC). However, little is known about the complex regulatory system of lncRNAs in GC. In this study, we systematically analyzed lncRNA and miRNA transcriptomic profiles of GC based on bioinformatics methods and experimental validation. An lncRNA-miRNA interaction network related to GC was constructed, and the nine crucial lncRNAs were identified. These 9 lncRNAs were found to be associated with the prognosis of GC patients by Cox proportional hazards regression analysis. Among them, the expression of lncRNA SNHG14 can affect the survival of GC patients as a potential prognostic marker. Moreover, it was shown that SNHG14 was involved in immune-related pathways and significantly correlated with immune cell infiltration in GC. Meanwhile, we found that SNHG14 affected immune function in many cancers, such as breast cancer and esophageal carcinoma. Such information revealed that SNHG14 may serve as a potential target for cancer immunotherapy. As well, our study could provide practical and theoretical guiding significance for clinical application of non-coding RNAs.

Research progress of circRNA in malignant tumour metabolic reprogramming.

Cancer is a multi-factor systemic malignant disease, which has seriously threatened human health and created a heavy burden on the world economy. Metabolic reprogramming, one of the important signs of malignant tumours, provides necessary nutrition for tumorigenesis and cancer development; thus, it has recently become a research hot spot, even though the metabolic mechanism is quite intricate. Circular RNA (circRNA) affects cancer cell metabolism through various molecular mechanisms, playing an important role in promoting or suppressing cancer. Because of the structure characteristics, circRNA is quite stable, and can be utilized as biomarkers. In this review, we analysed and summarized the characteristics and biological functions of circRNA and comprehensively reviewed and discussed the important role of circRNA in cancer metabolic reprogramming. This review will provide new ideas for developing new anti-cancer therapeutic targets, mining cancer diagnostic and prognostic markers, and will provide guidance for other researchers to design circRNA-related experiments and develop anti-tumour drugs.

HMGA2 as a potential molecular target in KMT2A-AFF1-positive infant acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) in infants is an intractable cancer in childhood. Although recent intensive chemotherapy progress has considerably improved ALL treatment outcome, disease cure is often accompanied by undesirable long-term side effects, and efficient, less toxic molecular targeting therapies have been anticipated. In infant ALL cells with KMT2A (MLL) fusion, the microRNA let-7b (MIRLET7B) is significantly downregulated by DNA hypermethylation of its promoter region. We show here that the expression of HMGA2, one of the oncogenes repressed by MIRLET7B, is reversely upregulated in infant ALL leukaemic cells, particularly in KMT2A-AFF1 (MLL-AF4) positive ALL. In addition to the suppression of MIRLET7B, KMT2A fusion proteins positively regulate the expression of HMGA2. HMGA2 is one of the negative regulators of CDKN2A gene, which encodes the cyclin-dependent kinase inhibitor p16(INK4A) . The HMGA2 inhibitor netropsin, when combined with demethylating agent 5-azacytidine, upregulated and sustained the expression of CDKN2A, which resulted in growth suppression of KMT2A-AFF1-expressing cell lines. This effect was more apparent compared to treatment with 5-azacytidine alone. These results indicate that the MIRLET7B-HMGA2-CDKN2A axis plays an important role in cell proliferation of leukaemic cells and could be a possible molecular target for the therapy of infant ALL with KMT2A-AFF1.

Hyaluronic acid methacrylate/laponite hydrogel loaded with BMP4 and maintaining its bioactivity for scar-free wound healing.

Scar-free wound healing is a challenging process due to the excessive deposition of extracellular matrix and collagen. To overcome this issue, hydrogels with superior biochemical and mechanical properties have been used in combination with medicinal compounds as wound dressings. In this study, a novel composite hydrogel consisting of double-crosslinked photocurable hyaluronic acid methacrylate (HAMA) and Laponite (Lap) loaded with bioactive bone morphogenetic protein 4 (BMP4) was developed and thoroughly characterized for its properties such as degradation, morphology, porosity, compression, skin adhesion and load release. The effect of the HAMA/Lap/BMP4 hydrogel was evaluated through both in vitro and in vivo experiments. In the in vivo rabbit ear-scar model, the HAMA/Lap/BMP4 hydrogel dressing was found to reduce scar-related expressions of α-SAM and decrease the ratio of collagen Ι/III in wounded tissue. Additionally, histopathological examination indicated that the HAMA/Lap/BMP4 hydrogel-treated groups exhibited enhanced wound repair and increased levels of collagen maintenance compared to other standard groups, ultimately leading to scarless wound healing. Therefore, this sustained-release photocurable HAMA/Lap/BMP4 hydrogel offers a therapeutic approach for scar-free wound healing.

Ginkgolic acid improves bleomycin-induced pulmonary fibrosis by inhibiting SMAD4 SUMOylation.

Idiopathic pulmonary fibrosis (IPF) is a refractory chronic respiratory disease with progressively exacerbating symptoms and a high mortality rate. There are currently only two effective drugs for IPF; thus, there is an urgent need to develop new therapeutics. Previous experiments have shown that ginkgolic acid (GA), as a SUMO-1 inhibitor, exerted an inhibitory effect on cardiac fibrosis induced by myocardial infarction. Regarding the pathogenesis of PF, previous studies have concluded that small ubiquitin-like modifier (SUMO) polypeptides bind multiple target proteins and participate in fibrosis of multiple organs, including PF. In this study, we found altered expression of SUMO family members in lung tissues from IPF patients. GA mediated the reduced expression of SUMO1/2/3 and the overexpression of SENP1 in a PF mouse model, which improved PF phenotypes. At the same time, the protective effect of GA on PF was also confirmed in the SENP1-KO transgenic mice model. Subsequent experiments showed that SUMOylation of SMAD4 was involved in PF. It was inhibited by TGF-ß1, but GA could reverse the effects of TGF-ß1. SENP1 also inhibited the SUMOylation of SMAD4 and then participated in epithelial-mesenchymal transition (EMT) downstream of TGF-ß1. We also found that SENP1 regulation of SMAD4 SUMOylation affected reactive oxygen species (ROS) production during TGF-ß1-induced EMT and that GA prevented this oxidative stress through SENP1. Therefore, GA may inhibit the SUMOylation of SMAD4 through SENP1 and participate in TGF-ß1-mediated pulmonary EMT, all of which reduce the degree of PF. This study provided potential novel targets and a new alternative for the future clinical testing in PF.

CRISPR/Cas9-3NLS/sgHMGA2@PDA nanosystem is the potential efficient gene editing therapy for gastric cancer with HMGA2 high expression.

Gene therapy is one of the target therapies with promising clinical use for gastric cancer (GC). However, the delivery of the CRISPR/Cas9/sgRNA (RNP) gene editing tool severely limits the practical therapeutic effect of GC. Therefore, it is a great challenge to develop an RNP delivery system that is simple to prepare and can rapidly encapsulate RNP while achieving high delivery and gene editing efficiency. We developed, for the first time, the CRISPR/Cas9@PDA nano-delivery system that can achieve high-efficiency delivery (95%) of CRISPR/Cas9-3NLS/sgHMGA2 and high-efficient HMGA2 gene editing (82%) of GC cells. In particular, the experiment's weak alkaline environment can not only protect the activity of CRISPR/Cas9-3NLS/sgHMGA2 but also trigger the self-polymerization of polydopamine (PDA). Meanwhile, the presence of KE in the CRISPR/Cas9 amino acid sequence can achieve the directional growth of PDA, thus forming a core-shell structure that protects CRISPR/Cas9-3NLS/sgHMGA2. This efficient CRISPR/Cas9-3NLS/sgHMGA2 delivery and HMGA2 gene editing ability has also been verified in mice, which can significantly inhibit tumor growth in mice. The success of building the delivery system and its ideal treating effect give hope to the efficacious treatment for the GC patients with HMGA2 high expression.

Long non-coding RNA HAND2-AS1 inhibits gastric cancer progression by suppressing TCEAL7 expression via targeting miR-769-5p.

Increasing evidence showed that Heart and Neural Crest Derivatives Expressed 2 antisense RNA 1 (HAND2-AS1) was involved in the progression of several cancers, but its expression and function in gastric cancer (GC) was rarely reported. HAND2-AS1 expression in GC tissues and cells was detected at first. Cell function assays were performed to investigate the biological roles of HAND2-AS1 in GC cells. Moreover, the genes regulated by HAND2-AS1 in GC were investigated. Downregulation of HAND2-AS1 was found in GC tissues and cell lines. HAND2-AS1 overexpression inhibited GC cell proliferation, invasion, and arrested cell cycle at G0/G1 phase, whereas HADN2-AS1 knockdown significantly promoted cell proliferation and invasion. Bioinformatic analysis showed there is a potential HADN2-AS1/microRNA-769-5p (miR-769-5p)/transcription elongation factor A like 7 (TCEAL7) axis in GC. Luciferase activity reporter system was used to confirm this link. Taken together, our study showed that HAND2-AS1 exerts its tumor suppressive role in GC via regulating miR-769-5p/TCEAL7.

CDK13-Mediated Cell Cycle Disorder Promotes Tumorigenesis of High HMGA2 Expression Gastric Cancer.

The inhibitor of CDK4/6 has been clinically used for treating certain types of cancer which are characterized by G0/G1 acceleration induced by the CDK4/6-RB1 pathway. On the contrary, the cell cycle-related molecules are abnormal in over 50% of the patients with gastric cancer (GC), but the efficiency of inhibiting CDK4/6 does not work well as it is expected. In our study, we found HMGA2 promotes GC through accelerating the S-G2/M phase transition, instead of G0/G1. We also found CDK13 is the direct target gene of HMGA2. Importantly, we analyzed 200 pairs of GC and the adjacent tissue and proved the positive relation between HMGA2 and CDK13; moreover, high expression of both genes predicts a poorer prognosis than the expression of single gene does. We explored the effect of the novel CDK12/13 inhibiting agent, SR-4835, on high HMGA2 expression GC and found inhibition of both genes jointly could reach a satisfied result. Therefore, we suggest that inhibition of CDK13 and HMGA2 simultaneously could be an effective strategy for high HMGA2 expression GC. To detect the expression of both genes simultaneously and individually could be of benefit to predict prognosis for GC.

Long Non-Coding RNA HAND2-AS1 Inhibits Growth and Migration of Gastric Cancer Cells Through Regulating the miR-590-3p/KCNT2 Axis.

INTRODUCTION: Long non-coding RNAs (lncRNAs) are regarded as crucial regulators for cancer initiation and progression. Heart and Neural Crest Derivatives Expressed 2 antisense RNA 1 (HAND2-AS1) was recently proposed to function as tumor suppressor in several human cancers. However, its role in gastric cancer (GC) remains unclear. METHODS: HAND2-AS1 expression in GC tissues and normal tissues was analyzed at GEPIA (a web server for gene expression profiling analysis). Moreover, RT-qPCR method was utilized to explore HAND2-AS1 expression in GC cells and normal cell. In vitro experiments were carried out using cell counting kit-8 assay, colony formation assay, and flow cytometry assay, respectively. Bioinformatic analysis and luciferase activity reporter assay were performed to identify the downstream targets of HAND2-AS1. RESULTS: We found HAND2-AS1 has decreased expression in both GC tissues and cells. Overexpression of HAND2-AS1 was able to inhibit GC cell proliferation, colony formation, but promote apoptosis. On the contrary, knockdown of HAND2-AS1 could cause the opposite effects on GC cells. Furthermore, HAND2-AS1 was shown to function as a competitive RNA that binds with microRNA-590-3p (miR-590-3p) to affect the expression of potassium sodium-activated channel subfamily T member 2 (KCNT2). DISCUSSION: Our results indicated the tumor suppressive role of HAND2-AS1 in GC. Also, the newly identified HAND2-AS1/miR-590-3p/KCNT2 axis will help us to understand the role of HAND2-AS1 in cancer.

DGCR6 at the proximal part of the DiGeorge critical region is involved in conotruncal heart defects.

Cardiac anomaly is one of the hallmarks of DiGeorge syndrome (DGS), observed in approximately 80% of patients. It often shows a characteristic morphology, termed as conotruncal heart defects. In many cases showing only the conotruncal heart defect, deletion of 22q11.2 region cannot be detected by fluorescence in situ hybridization (FISH), which is used to detect deletion in DGS. We investigated the presence of genomic aberrations in six patients with congenital conotruncal heart defects, who show no deletion at 22q11.2 in an initial screening by FISH. In these patients, no abnormalities were identified in the coding region of the TBX1 gene, one of the key genes responsible for the phenotype of DGS. However, when copy number alteration was analyzed by high-resolution array analysis, a small deletion or duplication in the proximal end of DiGeorge critical region was detected in two patients. The affected region contains the DGCR6 and PRODH genes. DGCR6 has been reported to affect the expression of the TBX1 gene. Our results suggest that altered dosage of gene(s) other than TBX1, possibly DGCR6, may also be responsible for the development of conotruncal heart defects observed in patients with DGS and, in particular, in those with stand-alone conotruncal heart defects.