Platelet Membrane-Camouflaged Silver Metal-Organic Framework Biomimetic Nanoparticles for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is characterized by high malignancy and limited treatment options. Given the pressing need for more effective treatments for TNBC, this study aimed to develop platelet membrane (PM)-camouflaged silver metal-organic framework nanoparticles (PM@MOF-Ag NPs), a biomimetic nanodrug. PM@MOF-Ag NP construction involved the utilization of 2-methylimidazole and silver nitrate to prepare silver metal-organic framework (MOF-Ag) NPs. The PM@MOF-Ag NPs, due to their camouflage, possess excellent blood compatibility, immune escape ability, and a strong affinity for 4T1 tumor cells. This enhances their circulation time in vivo and promotes the aggregation of PM@MOF-Ag NPs at the 4T1 tumor site. Importantly, PM@MOF-Ag NPs demonstrated promising antitumor activity in vitro and in vivo. We further revealed that PM@MOF-Ag NPs induced tumor cell death by overproducing reactive oxygen species and promoting cell apoptosis. Moreover, PM@MOF-Ag NPs enhanced apoptosis by upregulating the ratios of Bax/Bcl-2 and cleaved caspase3/pro-caspase3. Notably, PM@MOF-Ag NPs exhibited no significant organ toxicity, whereas the administration of MOF-Ag NPs resulted in liver inflammation compared to the control group.

METTL3-mediated m6A methylation of SLC38A1 stimulates cervical cancer growth.

The objective of this study was to better characterize the role of the glutamine transporter SLC38A1 in cervical cancer and explore the underlying mechanisms. Data from public databases and clinical cervical cancer tissue samples were used to assess the expression of SLC38A1 and its prognostic significance. Immunohistochemical staining, qRT-PCR, and Western blotting were used to evaluate the expression of relevant genes and proteins. Cell viability, cell cycle, apoptosis, and intracellular glutamine content were measured using CCK-8, flow cytometry, and biochemical assays. Additionally, the RNA immunoprecipitation (RIP) assay was used to examine the impact of METTL3/IGF2BP3 on the m6A modification of the SLC38A1 3'UTR. Both cervical cancer specimens and cells showed significantly increased expression of SLC38A1 and its expression correlated with an unfavorable prognosis. Knockdown of SLC38A1 inhibited cell viability and cell cycle progression, induced apoptosis, and suppressed tumor growth in vivo. Glutaminase-1 inhibitor CB-839 reversed the effects of SLC38A1 overexpression. METTL3 promoted m6A modification of SLC38A1 and enhanced its mRNA stability through IGF2BP3 recruitment. Moreover, METTL3 silencing inhibited cell viability, cell cycle progression, intracellular glutamine content, and induced apoptosis, but these effects were reversed by SLC38A1 overexpression. In conclusion, METTL3-mediated m6A methylation of SLC38A1 stimulates cervical cancer progression. SLC38A1 inhibition is a potential therapeutic strategy for cervical cancer.

A combination of a TLR7/8 agonist and an epigenetic inhibitor suppresses triple-negative breast cancer through triggering anti-tumor immune.

BACKGROUND: Combination therapy involving immune checkpoint blockade (ICB) and other drugs is a potential strategy for converting immune-cold tumors into immune-hot tumors to benefit from immunotherapy. To achieve drug synergy, we developed a homologous cancer cell membrane vesicle (CM)-coated metal-organic framework (MOF) nanodelivery platform for the codelivery of a TLR7/8 agonist with an epigenetic inhibitor. METHODS: A novel biomimetic codelivery system (MCM@UN) was constructed by MOF nanoparticles UiO-66 loading with a bromodomain-containing protein 4 (BRD4) inhibitor and then coated with the membrane vesicles of homologous cancer cells that embedding the 18 C lipid tail of 3M-052 (M). The antitumor immune ability and tumor suppressive effect of MCM@UN were evaluated in a mouse model of triple-negative breast cancer (TNBC) and in vitro. The tumor immune microenvironment was analyzed by multicolor immunofluorescence staining. RESULTS: In vitro and in vivo data showed that MCM@UN specifically targeted to TNBC cells and was superior to the free drug in terms of tumor growth inhibition and antitumor immune activity. In terms of mechanism, MCM@UN blocked BRD4 and PD-L1 to prompt dying tumor cells to disintegrate and expose tumor antigens. The disintegrated tumor cells released damage-associated molecular patterns (DAMPs), recruited dendritic cells (DCs) to efficiently activate CD8+ T cells to mediate effective and long-lasting antitumor immunity. In addition, TLR7/8 agonist on MCM@UN enhanced lymphocytes infiltration and immunogenic cell death and decreased regulatory T-cells (Tregs). On clinical specimens, we found that mature DCs infiltrating tumor tissues of TNBC patients were negatively correlated with the expression of BRD4, which was consistent with the result in animal model. CONCLUSION: MCM@UN specifically targeted to TNBC cells and remodeled tumor immune microenvironment to inhibit malignant behaviors of TNBC.

CMYC-initiated HNF1A-AS1 overexpression maintains the stemness of gastric cancer cells.

Cancer stem cells (CSCs) are believed to be responsible for cancer metastasis and recurrence due to their self-renewal ability and resistance to treatment. However, the mechanisms that regulate the stemness of CSCs remain poorly understood. Recently, evidence has emerged suggesting that long non-coding RNAs (lncRNAs) play a crucial role in regulating cancer cell function in different types of malignancies, including gastric cancer (GC). However, the specific means by which lncRNAs regulate the function of gastric cancer stem cells (GCSCs) are yet to be fully understood. In this study, we investigated a lncRNA known as HNF1A-AS1, which is highly expressed in GCSC s and serves as a critical regulator of GCSC stemness and tumorigenesis. Our experiments, both in vitro and in vivo, demonstrated that HNF1A-AS1 maintained the stemness of GC cells. Further analysis revealed that HNF1A-AS1, transcriptionally activated by CMYC, functioned as a competing endogenous RNA by binding to miR-150-5p to upregulate ß-catenin expression. This in turn facilitated the entry of ß-catenin into the nucleus to activate the Wnt/ß-catenin pathway and promote CMYC expression, thereby forming a positive feedback loop that sustained the stemness of GCSCs. We also found that blocking the Wnt/ß-catenin pathway effectively inhibited the function of HNF1A-AS1, ultimately resulting in the inhibition of GCSC stemness. Taken together, our results demonstrated that HNF1A-AS1 is a regulator of the stemness of GCSCs and could serve as a potential marker for targeted GC therapy.

LncRNA LY6E-DT and its encoded metastatic-related protein play oncogenic roles via different pathways and promote breast cancer progression.

Abnormal long noncoding RNA (lncRNA) expression plays an important role in tumor invasion and metastasis. Here, we show that lncRNA LY6E divergent transcript (LY6E-DT) levels are increased in breast cancer (BC) tissues. Transcription factor SP3 binds directly to the LY6E-DT promoter, activating its transcription. Moreover, LY6E-DT N6-methyladenosine modification by methyltransferase-like protein 14 (METTL14) promotes its expression, dependent on the "reader" insulin-like growth factor 2 mRNA binding protein 1(IGF2BP1)-dependent pathway. Notably, we discovered that the lncRNA LY6E-DT encodes a conserved 153-aa protein, "Metastatic-Related Protein" (MRP). Both LY6E-DT and MRP promote BC invasion and metastasis, and MRP expression could distinguish BC patients with lymph node metastasis from those without. Mechanistically, MRP binds heterogeneous nuclear ribonucleoproteins C1/C2 (HNRNPC), enhancing the interaction between HNRNPC and epidermal growth factor receptor (EGFR) mRNA, increasing EGFR mRNA stability and protein expression and subsequently activating the phosphatidylinositol 3­kinase/protein kinase B signaling (PI3K) pathway. LncRNA LY6E-DT promotes the interaction between Y box binding protein 1 (YBX1) and importin α1 and increases YBX1 protein entry into the nucleus, where it transcriptionally activates zinc finger E-box-binding homeobox 1(ZEB1). Our findings uncover a novel regulatory mechanism underlying BC invasion orchestrated by LY6E-DT and its encoded MRP.

Mechanistic insights into UHRF1­mediated DNA methylation by structure­based functional clarification of UHRF1 domains (Review).

Epigenetic modification is crucial for transmitting genetic information, while abnormalities in DNA methylation modification are primarily associated with cancer and neurological diseases. As a multifunctional epigenetic modifier, ubiquitin like with PHD and ring finger domains 1 (UHRF1) mainly affects cell energy metabolism and cell cycle control. It also inhibits the transcription of tumor suppressor genes through DNA and/or histone methylation modifications, promoting the occurrence and development of cancer. Therefore, comprehensively understanding the molecular mechanism of the epigenetic modification of UHRF1 in tumors will help identify targets for inhibiting the expression and function of UHRF1. Notably, each domain of UHRF1 functions as a whole and differently. Thus, the abnormality of any domain can lead to a change in phenotype or disease. However, the specific regulatory mechanism and proteins of each domain have not been fully elucidated. The present review aimed to contribute to the study of the regulatory mechanism of UHRF1 to a greater extent in different cancers and provide ideas for drug research by clarifying the function of UHRF1 domains.

ETS-1-activated LINC01016 over-expression promotes tumor progression via suppression of RFFL-mediated DHX9 ubiquitination degradation in breast cancers.

Long non-coding RNAs (lncRNAs) are key regulators during the development of breast cancer (BC) and thus may be viable treatment targets. In this study, we found that the expression of the long intergenic non-coding RNA 01016 (LINC01016) was significantly higher in BC tissue samples with positive lymph node metastasis. LINC01016, which is activated by the transcription factor ETS-1, contributes to the overt promotion of cell proliferation activity, enhanced cell migratory ability, S phase cell cycle arrest, and decreased apoptosis rate. By RNA pull-down assays and mass spectrometry analyses, we determined that LINC01016 competitively bound and stabilized DHX9 protein by preventing the E3 ubiquitin ligase RFFL from binding to DHX9, thereby inhibiting DHX9 proteasomal degradation. This ultimately led to an increase in intracellular DHX9 expression and activated PI3K/AKT signaling, with p-AKT, Bcl-2, and MMP-9 involvement. This is the first study to reveal that the LINC01016/DHX9/PI3K/AKT axis plays a critical role in the progression of BC, and thus, LINC01016 may serve as a potential therapeutic target for patients with BC.

Bioengineered stem cell membrane functionalized nanoparticles combine anti-inflammatory and antimicrobial properties for sepsis treatment.

BACKGROUND: Sepsis is a syndrome of physiological, pathological and biochemical abnormalities caused by infection. Although the mortality rate is lower than before, many survivors have persistent infection, which means sepsis calls for new treatment. After infection, inflammatory mediators were largely released into the blood, leading to multiple organ dysfunction. Therefore, anti-infection and anti-inflammation are critical issues in sepsis management. RESULTS: Here, we successfully constructed a novel nanometer drug loading system for sepsis management, FZ/MER-AgMOF@Bm. The nanoparticles were modified with LPS-treated bone marrow mesenchymal stem cell (BMSC) membrane, and silver metal organic framework (AgMOF) was used as the nanocore for loading FPS-ZM1 and meropenem which was delivery to the infectious microenvironments (IMEs) to exert dual anti-inflammatory and antibacterial effects. FZ/MER-AgMOF@Bm effectively alleviated excessive inflammatory response and eliminated bacteria. FZ/MER-AgMOF@Bm also played an anti-inflammatory role by promoting the polarization of macrophages to M2. When sepsis induced by cecal ligation and puncture (CLP) challenged mice was treated, FZ/MER-AgMOF@Bm could not only reduce the levels of pro-inflammatory factors and lung injury, but also help to improve hypothermia caused by septic shock and prolong survival time. CONCLUSIONS: Together, the nanoparticles played a role in combined anti-inflammatory and antimicrobial properties, alleviating cytokine storm and protecting vital organ functions, could be a potential new strategy for sepsis management.

PTPN14 promotes gastric cancer progression by PI3KA/AKT/mTOR pathway.

Gastric cancer is a high molecular heterogeneous disease with a poor prognosis. Although gastric cancer is a hot area of medical research, the mechanism of gastric cancer occurrence and development is still unclear. New strategies for treating gastric cancer need to be further explored. Protein tyrosine phosphatases play vital roles in cancer. A growing stream of studies shows that strategies or inhibitors targeting protein tyrosine phosphatases have been developed. PTPN14 belongs to the protein tyrosine phosphatase subfamily. As an inert phosphatase, PTPN14 has very poor activity and mainly functions as a binding protein through its FERM (four-point-one, ezrin, radixin, and moesin) domain or PPxY motif. The online database indicated that PTPN14 may be a poor prognostic factor for gastric cancer. However, the function and underlying mechanism of PTPN14 in gastric cancer remain unclear. We collected gastric cancer tissues and detected the expression of PTPN14. We found that PTPN14 was elevated in gastric cancer. Further correlation analysis indicated that PTPN14 was relevant with the T stage and cTNM (clinical tumor node metastasis classification) stage. The survival curve analysis showed that gastric cancer patients with higher PTPN14 expression had a shorter survival time. In addition, we illustrated that CEBP/ß (CCAAT enhanced binding protein beta) could transcriptionally activate PTPN14 expression in gastric cancer. The highly expressed PTPN14 combined with NFkB (nuclear factor Kappa B) through its FERM domain and accelerated NFkB nucleus translocation. Then, NFkB promoted the transcription of PI3KA and initiated the PI3KA/AKT/mTOR pathway to promote gastric cancer cell proliferation, migration, and invasion. Finally, we established mice models to validate the function and the molecular mechanism of PTPN14 in gastric cancer. In summary, our results illustrated the function of PTPN14 in gastric cancer and demonstrated the potential mechanisms. Our findings provide a theoretical basis to better understand the occurrence and development of gastric cancer.

Successful treatment of pulmonary hypertension in a neonate with bronchopulmonary dysplasia: A case report and literature review.

BACKGROUND: Pulmonary hypertension (PH) is a severe complication of bronchopulmonary dysplasia (BPD) in premature neonates and is closely related to prognosis. However, there is no effective and safe treatment for PH due to BPD in infants. Successful treatment for cases of BPD-associated PH with Tadalafil combined with bosentan is rare. This case may make a significant contribution to the literature because PH is difficult to manage as a serious complication of BPD in preterm infants. Mortality is high, especially when it is complicated by heart failure. CASE SUMMARY: An extremely premature neonate with a gestational age of 26+5 wk and birth weight of 0.83 kg was diagnosed with BPD associated with PH; oral sildenafil did not improve the PH. The infant experienced sudden cardiac arrest and serious heart failure with severe PH. After a series of treatments, including cardiopulmonary resuscitation, mechanical ventilation, and inhaled nitric oxide (iNO), the respiratory and circulatory status improved but the pulmonary artery pressure remained high. Then oral sildenafil was replaced with oral tadalafil and bosentan; pulmonary artery pressure improved, and the infant recovered at our hospital. After 2 years of follow-up, she is in good condition, without any cardiovascular complications. CONCLUSION: INO can effectively improve the respiratory and circulatory status of infants with PH associated with premature BPD. B-type natriuretic peptide should be routinely measured during hospitalization to evaluate the risk and prognosis of BPD-associated PH in preterm infants. Tadalafil combined with bosentan for the treatment of PH associated with premature BPD was better than sildenafil in this case. Further studies are needed to explore the efficacy and safety of different vasodilators in the treatment of PH associated with premature BPD.

Telomerase reverse transcriptase promotes angiogenesis in neonatal rats after hypoxic-ischemic brain damage.

Background: Angiogenesis is an endogenous repair mechanism following hypoxic-ischemic brain damage (HIBD). Interestingly, recent studies have shown that angiogenesis can be regulated by telomerase reverse transcriptase (TERT), a critical component of telomerase. As telomerase reverse transcriptase can promote angiogenesis after stroke, we hypothesized that it could also promote angiogenesis after HIBD. To test this hypothesis, we developed in vivo and in vitro HIBD models in neonatal rats. Methods: TERT was overexpressed by lentivirus and adenovirus infection, and levels were measured using quantitative real-time polymerase chain reaction. We used a cell counting kit to quantify the proliferation rate of brain microvascular endothelial cells (BMECs), and immunofluorescence staining to measure CD34 expression levels. A microvessel formation assay was used to evaluate angiogenesis. Blood-brain barrier (BBB) integrity was assessed using immunohistochemical staining for ZO-1 and Evans Blue staining. Lastly, the expression level of Notch-1 was measured by western blotting. Results: Overexpression of TERT promoted the proliferation of BMECs after hypoxic-ischemic damage in vitro. TERT overexpression increased the formation of microvessels in the neonatal brain after HIBD both in vivo and in vitro. Overexpression of TERT improved BBB integrity in the brains of neonatal rats after HIBD. In addition, the expression level of Notch-1 was increased in BMECs following oxygen glucose deprivation, and overexpression of TERT further increased Notch-1 expression levels in BMECs following oxygen glucose deprivation. Discussion: Our results reveal that telomerase reverse transcriptase promotes angiogenesis and maintains the integrity of the blood-brain barrier after neonatal hypoxic-ischemic brain damage. Furthermore, the Notch-1 signaling pathway appears to contribute to the angiogenic function of telomerase reverse transcriptase. This protective effect of telomerase reverse transcriptase opens new horizons for future investigations aimed at uncovering the full potential of telomerase reverse transcriptase as a promising new target for the treatment of hypoxic-ischemic encephalopathy.

Combined Microbiome and Metabolome Analysis Reveals a Novel Interplay Between Intestinal Flora and Serum Metabolites in Lung Cancer.

As the leading cause of cancer death, lung cancer seriously endangers human health and quality of life. Although many studies have reported the intestinal microbial composition of lung cancer, little is known about the interplay between intestinal microbiome and metabolites and how they affect the development of lung cancer. Herein, we combined 16S ribosomal RNA (rRNA) gene sequencing and liquid chromatography-mass spectrometry (LC-MS) technology to analyze intestinal microbiota composition and serum metabolism profile in a cohort of 30 lung cancer patients with different stages and 15 healthy individuals. Compared with healthy people, we found that the structure of intestinal microbiota in lung cancer patients had changed significantly (Adonis, p = 0.021). In order to determine how intestinal flora affects the occurrence and development of lung cancer, the Spearman rank correlation test was used to find the connection between differential microorganisms and differential metabolites. It was found that as thez disease progressed, L-valine decreased. Correspondingly, the abundance of Lachnospiraceae_UCG-006, the genus with the strongest association with L-valine, also decreased in lung cancer groups. Correlation analysis showed that the gut microbiome and serum metabolic profile had a strong synergy, and Lachnospiraceae_UCG-006 was closely related to L-valine. In summary, this study described the characteristics of intestinal flora and serum metabolic profiles of lung cancer patients with different stages. It revealed that lung cancer may be the result of the mutual regulation of L-valine and Lachnospiraceae_UCG-006 through the aminoacyl-tRNA biosynthesis pathway, and proposed that L-valine may be a potential marker for the diagnosis of lung cancer.

Telomerase reverse transcriptase (TERT) promotes neurogenesis after hypoxic-ischemic brain damage in neonatal rats.

OBJECTIVE: Neonatal hypoxic-ischemic encephalopathy (HIE) endangers quality of life in children, and curative attempts are rarely effective. Neurogenesis plays an important role in neural repair following brain damage. This study aimed to investigate the role of telomerase reverse transcriptase (TERT) in neurogenesis after neonatal hypoxic-ischemic brain damage (HIBD). METHODS: Neonatal HIBD models were established in vivo (Sprague-Dawley rats, 7 days old) and in vitro (cultured neural stem cells, NSCs). Lentivirus and adenovirus transfection was used to induce TERT overexpression. Expression of TERT was detected by quantitative real-time PCR and immunofluorescence staining. NSCs apoptosis and proliferation were measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and cell counting assays, respectively. Migration and differentiation of NSCs were assessed by western blotting and immunofluorescence staining. Morris water maze test and modified neurological severity scores were conducted to evaluate the neurological function of rats. RESULTS: Overexpression of TERT attenuated apoptosis of NSCs; promoted proliferation, migration, and differentiation of NSCs; and induced myelination in the brains of neonatal rats after HIBD. Moreover, it reduced the impairment of learning, memory, and neurological function after HIBD in neonatal rats. In vitro findings indicated that the expression of Gli1 was increased after OGD, and overexpression of TERT further increased the expression of Gli1 in NSCs after OGD. DISCUSSION: TERT promotes neurogenesis and decreases neurological function injury after HIBD in neonatal rats. This neuroprotective pathway may provide a basis for developing therapeutic strategies for neonatal HIE. Furthermore, TERT may represent a target during neural injury and repair in patients with various diseases affecting the nervous system.

CircKDM4B suppresses breast cancer progression via the miR-675/NEDD4L axis.

Increasing studies have indicated that circular RNAs (circRNAs) play pivotal roles in various cancers. Here, we aimed to explore the roles of circRNAs in breast cancer. We identified a novel circRNA circKDM4B (hsa_circ_0002926) by whole-transcriptome sequencing and validated this by Real-time quantitative polymerase chain reaction (RT-qPCR) and Sanger sequencing. It was significantly decreased in breast cancer tissues compared with adjacent non-tumor tissues. Furthermore, circKDM4B, which is mainly localized in the cytoplasm, was more resistant to actinomycin D or ribonuclease R than its linear transcript KDM4B. In addition, the overexpression of circKDM4B inhibited cell migration and invasion in vitro, while knockdown of circKDM4B induced the opposite effects. In vivo, circKDM4B suppressed tumor growth and metastasis. Additionally, circKDM4B inhibited migration and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro and angiogenesis in vivo. Mechanically, circKDM4B sponged miR-675 to upregulate the expression of NEDD4-like E3 ubiquitin protein ligase (NEDD4L), which catalyzes ubiquitination of PI3KCA, thereby inhibiting PI3K/AKT and VEGFA secretion. Collectively, these findings uncovered the tumor-suppressor role of circKDM4B in breast cancer, especially in angiogenesis and tumor metastasis, indicating that circKDM4B could be a potential therapeutic target for breast cancer progression.

Low Glucose-Induced Overexpression of HOXC-AS3 Promotes Metabolic Reprogramming of Breast Cancer.

Breast cancer is the most common malignancy in women worldwide. However, the mechanisms underlying breast cancer energy metabolism and progression remain obscure. Cancer cells rapidly adapt to microenvironments with fluctuating nutrient levels. Here, we characterized a long noncoding RNA (lncRNA), HOXC-AS3, which is activated upon glucose deprivation to trigger a nutrient-stress response and a switch in glucose metabolism. Upregulation of HOXC-AS3 in breast cancer was identified by in published microarray and RNA-sequencing datasets, and then confirmed by qRT-PCR in fresh breast cancer tissues. Glucose deprivation induced HOXC-AS3 overexpression in a dose- and time-dependent manner in breast cancer cells. Gain- and loss-of-function experiments in vitro and in vivo showed that HOXC-AS3 triggers energy metabolism reprogramming. ChIRP-mass spectrometry and unique molecular identifier RNA immunoprecipitation and high-throughput sequencing (UMI RIP-seq) identified binding motifs of HOXC-AS3 with SIRT6. HOXC-AS3 selectively antagonized SIRT6-mediated H3K9ac deacetylation of glycolysis-related genes. Moreover, HOXC-AS3 binding to SIRT6 prevented contact inhibition of HIF1α, leading to reprogramming of metabolic pathways. In addition, HOXC-AS3, SP1, and miR-1224-5p formed a positive feedback loop to maintain cancer-promoting signals. Furthermore, administration of anti-HOXC-AS3-motif-RNAs effectively blocked the function of HOXC-AS3, ultimately suppressing breast cancer progression. These results reveal a critical role for HOXC-AS3 in regulating the metabolic reprogramming of breast cancer cells under metabolic stress. Use of an anti-HOXC-AS3-motif RNA mixture may be a promising strategy to suppress breast cancer progression. SIGNIFICANCE: HOXC-AS3 is a low glucose-activated long noncoding RNA that triggers metabolic reprogramming in breast cancer cells to adapt to nutrient stress, identifying HOXC-AS3 as a potential therapeutic target for breast cancer treatment.

lncRNA THAP7-AS1, transcriptionally activated by SP1 and post-transcriptionally stabilized by METTL3-mediated m6A modification, exerts oncogenic properties by improving CUL4B entry into the nucleus.

Long noncoding RNAs (lncRNAs) are dysregulated in different cancer types, and thus have emerged as important regulators of the initiation and progression of human cancers. However, the biological functions and the underlying mechanisms responsible for their functions in gastric cancer (GC) remain poorly understood. Here, by lncRNA microarray, we identified 1414 differentially expressed lncRNAs, among which THAP7-AS1 was significantly upregulated in GC tissues compared with non-tumorous gastric tissues. High expression of THAP7-AS1 was correlated with positive lymph node metastasis and poorer prognosis. SP1, a transcription factor, could bind directly to the THAP7-AS1 promoter region and activate its transcription. Moreover, the m6A modification of THAP7-AS1 by METTL3 enhanced its expression depending on the "reader" protein IGF2BP1-dependent pathway. THAP7-AS1 promoted GC cell progression. Mechanistically, THAP7-AS1 interacted with the 1-50 Amino Acid Region (nuclear localization signal) of CUL4B through its 1-442 nt Sequence, and it promoted interaction between nuclear localization signal (NLS) and importin α1, and improved the CUL4B protein entry into the nucleus, repressing miR-22-3p and miR-320a expression by CUL4B-catalyzed H2AK119ub1 and the EZH2-mediated H3K27me3, subsequently activating PI3K/AKT signaling pathway to promote GC progression. Moreover, LV-sh-THAP7-AS1 treatment could suppress GC growth, invasion and metastasis, indicating that THAP7-AS1 may act as a promising molecular target for GC therapies. Taken together, our results show that THAP7-AS1, transcriptionally activated by SP1 and then modified by METTL3-mediated m6A, exerts oncogenic functions, by promoting interaction between NLS and importin α1 and then improving the CUL4B protein entry into the nucleus to repress the transcription of miR-22-3p and miR-320a.

Long noncoding RNA lnc-LEMGC combines with DNA-PKcs to suppress gastric cancer metastasis.

Long non-coding RNAs (lncRNAs) play important roles in cancer development and progression; however, their contributions to gastric cancer metastasis remain largely unknown. By lncRNA microarray screening, our study showed that 453 lncRNAs are dysregulated in gastric cancer tissues with or without lymph node metastasis, of which lnc-LEMGC ranks as one of the most significantly downregulated lncRNAs. Lnc-LEMGC inhibited cell migration and invasion both in vitro and in vivo, by combining with protein DNA-PKcs. Importantly, nucleotides 1300-1800 of lnc-LEMGC prevented DNA-PKcs phosphorylation of serine 2056 and partially abrogated the effects of downstream effectors, ErbB1, SRC and protein tyrosine kinase 2 (FAK), in the epidermal growth factor receptor (EGFR) pathway. The results of this study extend our knowledge of lncRNA's molecular mechanisms, in which lnc-LEMGC functions by directly suppressing the phosphorylation of its combined protein DNA-PKcs and inactivating the DNA-PKcs downstream EGFR signaling.

Aberrant promoter hypermethylation inhibits RGMA expression and contributes to tumor progression in breast cancer.

Breast cancer (BC) is the most common cancer in women worldwide, and the exploration of aberrantly expressed genes might clarify tumorigenesis and help uncover new therapeutic strategies for BC. Although RGMA was recently recognized as a tumor suppressor gene, its detailed biological function and regulation in BC remain unclear. Herein, we found that RGMA was downregulated in BC tissues compared with non-tumorous breast tissues, particularly in metastatic BC samples, and that patients with low RGMA expression manifested a poorer prognosis. Furthermore, DNMT1 and DNMT3A were found to be recruited to the RGMA promoter and induced aberrant hypermethylation, resulting in downregulation of RGMA expression in BC. In contrast, RGMA overexpression suppressed BC cell proliferation and colony-formation capabilities and increased BC cell apoptosis. Furthermore, RGMA knockdown accelerated BC cell proliferation and suppressed cellular apoptosis in vitro and in vivo. Reversal of RGMA promoter methylation with 5-Aza-CdR restored RGMA expression and blocked tumor growth. Overall, DNMT1- and DNMT3A-mediated RGMA promoter hypermethylation led to downregulation of RGMA expression, and low RGMA expression contributed to BC growth via activation of the FAK/Src/PI3K/AKT-signaling pathway. Our data thus suggested that RGMA might be a promising therapeutic target in BC.

ELK1-induced up-regulation of KIF26B promotes cell cycle progression in breast cancer.

KIF26B is a member of the kinesin superfamily that is up-regulated in various tumors, including breast cancer (BC), which can promote tumor progression. This study aimed to investigate the potential function of KIF26B in BC, and the underlying mechanisms, focusing mainly on cell proliferation. KIF26B expression was examined in BC tissue samples obtained from 99 patients. Then, we performed MTS, EdU and flow cytometry assays to detect cell proliferation, and western blotting to measure the expression of cell cycle-related proteins in MDA-MB-231 and MDA-MB-468 cells following KIF26B knockdown. Promoter analysis was used to study the upstream regulatory mechanism of KIF26B. KIF26B was upregulated in BC tissues. High expression of KIF26B was associated with clinicopathological parameters, such as positive lymph node metastasis, higher tumor grade, and higher proliferative index in BC. Furthermore, knockdown of KIF26B expression inhibited MDA-MB-231 and MDA-MB-468 cell proliferation, arresting cells in the G1 phase of the cell cycle in vitro. Similarly, KIF26B silencing decreased the expression levels of Wnt, ß-catenin, and cell cycle-related proteins such as c-Myc, cyclin D1, and cyclin-dependent kinase 4, while increasing the expression of p27. Moreover, ELK1 could bind to the core promoter region of KIF26B and activate its transcription. KIF26B acts as an oncogene in BC by regulating multiple proteins involved in the cell cycle. ELK1 activates KIF26B transcription.