Research progress of calcium carbonate nanomaterials in cancer therapy: challenge and opportunity.

Cancer has keeping the main threat to the health of human being. Its overall survival rate has shown rare substantial progress in spite of the improving diagnostic and treatment techniques for cancer in recent years. Indeed, such classic strategies for malignant tumor as surgery, radiation and chemotherapy have been developed and bring more hope to the patients, but still been accompanied by certain limitations, which include the challenge of managing large wound sizes, systemic toxic side effects, and harmful to the healthy tissues caused by imprecise alignment with tumors in radiotherapy. Furthermore, immunotherapy exhibits a limited therapeutic effect in advanced tumors which is reported only up to 25%-30%. The combination of nanomaterials and cancer treatment offers new hope for cancer patients, demonstrating strong potential in the field of medical research. Among the extensively utilized nanomaterials, calcium carbonate nanomaterials (CCNM) exhibit a broad spectrum of biomedical applications due to their abundant availability, cost-effectiveness, and exceptional safety profile. CCNM have the potential to elevate intracellular Ca2+ levels in tumor cells, trigger the mitochondrial damage and ultimately lead to tumor cell death. Moreover, compared with other types of nanomaterials, CCNM exhibit remarkable advantages as delivery systems owing to their high loading capacity, biocompatibility and biodegradability. The purpose of this review is to provide an overview of CCNM synthesis, focusing on summarizing its diverse roles in cancer treatment and the benefits and challenges associated with CCNM in cancer therapy. Hoping to present the significance of CCNM as for the clinical application, and summarize information for the design of CCNM and other types of nanomaterials in the future.

An Autophagy-Associated Prognostic Gene Signature for Breast Cancer.

Autophagy is closely related to breast cancer and has the dual role of promoting and inhibiting the progression of breast cancer. In this study, we aimed to establish an autophagy-related gene signature for the prognosis of breast cancer. A gene signature composed of the eight most survival-relevant autophagy-associated genes was identified by least absolute shrinkage and selection operator (LASSO) regression analysis. A risk score was calculated based on the gene signature, which divided breast cancer patients into low- or high-risk groups and showed good and poor prognosis, respectively. The risk score displayed good prognostic performance in both the training cohort (TCGA, 1-10-year AUC > 0.63) and the validation cohort (GEO, 1-10-year AUC > 0.66). The multivariate Cox regression and stratified analysis revealed that the risk score was an independent prognostic factor for breast cancer patients. Moreover, the high-risk score was associated with higher infiltration of neutrophils and M2-polarized macrophages, and lower infiltration of resting memory CD4+ T cells, CD8+ T cells, and NK cells. Finally, the high-risk score was associated with myc target, glycolysis, and mTORC1 signaling. The risk score developed based on the autophagy-associated gene signature was an independent prognostic biomarker for breast cancer.

Identification of a key ceRNA network associated with ferroptosis in gastric cancer.

Ferroptosis, a newly discovered irondependent form of regulated cell death caused by excessive accumulation of lipid peroxides, is linked to the development and treatment response of various types of cancer, including gastric cancer (GC). Noncoding RNAs (ncRNAs), as key regulators in cancer, have both oncogenic and tumor suppressive roles. However, studies on ferroptosis-related ncRNA networks in GC are still lacking. Here, we first identified 61 differentially expressed genes associated with ferroptosis in GC by computing and analyzing gene expression profile of tumor and normal tissues for GC. Then, upstream lncRNAs and miRNAs interacting with them were found through miRNet and miRBase databases, and hub lncRNAs and miRNAs were obtained through topological analysis. Finally, the ceRNA regulatory network linked to ferroptosis in GC was established, which includes two ferroptosis marker genes (TXNIP and TSC22D3), one driver gene (GABARAPL1), and one suppressor gene (CAV1). Kaplan-Meier survival analysis showed that changes in the expression of these genes were associated with the survival of GC patients. Furthermore, our study revealed that this ceRNA network may influence the progression of GC by regulating ferroptosis process. These results will help experimental researchers to design an experiment study to further explore the roles of this regulatory network in GC ferroptosis.

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.

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.

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.

CTCF-induced upregulation of LINC01207 promotes gastric cancer progression via miR-1301-3p/PODXL axis.

BACKGROUND: Long non coding RNAs (lncRNAs) have been validated to be involved in the complicated biological processes during tumor progression. LINC01207 has been identified as an oncogene in several cancer types. However, the function of LINC01207 and its underlying molecular mechanism in gastric cancer (GC) are poorly understood. METHODS: The expression level of LINC01207, miR-1301-3p and PODXL mRNA was detected in GC tissues and cells by RT-qPCR. The level of PODXL protein was examined by western blot. Colony formation assay, EdU assay, TUNEL assay, caspase-3 activity test and transwell assays were carried out to analyze the effect of LINC01207 on GC cell proliferation, apoptosis, migration and invasion. The interaction between RNAs was confirmed by luciferase reporter assay, RNA pull-down assay and RIP assay. RESULTS: LINC01207 was expressed at high level in GC tissues and cells. Silencing of LINC01207 impaired GC cell proliferation, migration and invasion but promoted cell apoptosis. Mechanistically, LINC01207 acted as a ceRNA by sponging miR-1301-3p to upregulate PODXL. Besides, miR-1301-3p silencing or PODXL overexpression could abolish the inhibitory effect of LINC01207 knockdown on GC cell growth and migration. CCCTC-binding factor (CTCF) could transcriptionally activate LINC01207 in GC cells. CONCLUSIONS: CTCF-induced activation of LINC01207 contributes to GC progression through regulating miR-1301-3p/PODXL axis.

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.

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.

Multiple genetic variants in adolescent patients with left ventricular noncompaction cardiomyopathy.

BACKGROUND: Left ventricular noncompaction cardiomyopathy (LVNC) is a primary cardiomyopathy with an unclear aetiology. The clinical symptoms range from asymptomatic to heart failure, arrhythmias and sudden cardiac death. This study aimed to characterize the genetic features and clinical outcomes of LVNC who underwent heart transplantation (HTx) to reveal the potential genetic pathogenesis. METHODS AND RESULTS: We recruited 16 cases who underwent HTx in our hospital. Exome-sequencing was performed to reveal genetic background. Clinical information and histopathology features of patients were investigated. Gene expression profiling of tissue fibrosis were evaluated by quantitative PCR. The median age of patients was 21 years. Of the 16 patients, 14 harboured multiple gene variants involved in LVNC. Ten of the patients harboured biallelic variants and/or truncating variants. Young patients (<18) with biallelic variants and/or truncating variants and lower LVEF (<45%) at initial symptom deteriorated quickly. Except for noncompaction myocardium, myocardial fibrosis was a remarkable pathological feature, and gene profiles related to immune inflammation and extracellular matrix remodelling were upregulated. CONCLUSIONS: This study showed that multiple pathologic variants were underlie genetic mechanism of LVNC who in high risks, suggesting that genetic screening should be applied to the diagnosis of LVNC. LVNC patient with multiple variants should be considered carefully follow-up. Genetics involved in the phenotype and cardiac fibrosis, and is the major causing for LVNC.

Two NAC transcription factors from Caragana intermedia altered salt tolerance of the transgenic Arabidopsis.

BACKGROUND: Plants are continuously challenged by different environment stresses, and they vary widely in their adjustability. NAC (NAM, ATAF and CUC) transcription factors are known to be crucial in plants tolerance response to abiotic stresses, such as drought and salinity. ANAC019, ANAC055, and ANAC072, belong to the stress-NAC TFs, confer the Arabidopsis abiotic stress tolerance. RESULTS: Here we isolated two stress-responsive NACs, CiNAC3 and CiNAC4, from Caragana intermedia, which were induced by ABA and various abiotic stresses. Localization assays revealed that CiNAC3 and CiNAC4 localized in the nuclei, consistent with their roles as transcription factors. Histochemistry assay using Pro(CiNAC4)::GUS transgenic Arabidopsis showed that the expression of the GUS reporter was observed in many tissues of the transgenic plants, especially in the root vascular system. Overexpression of CiNAC3 and CiNAC4 reduced ABA sensitivity during seed germination, and enhanced salt tolerance of the transgenic Arabidopsis. CONCLUSIONS: We characterised CiNAC3 and CiNAC4 and found that they were induced by numerous abiotic stresses and ABA. GUS histochemical assay of CiNAC4 promoter suggested that root, flower and local damaged tissues were the strongest stained tissues. Overexpression assay revealed that CiNAC4 play essential roles not only in promoting lateral roots formation, but also in responding to salinity and ABA treatment of Arabidopsis.