Acyltransferase zinc finger DHHC-type containing 2 aggravates gastric carcinoma growth by targeting Nrf2 signaling: A mechanism-based multicombination bionic nano-drug therapy.

The significant regulatory role of palmitoylation modification in cancer-related targets has been demonstrated previously. However, the biological functions of Nrf2 in stomach cancer and whether the presence of Nrf2 palmitoylation affects gastric cancer (GC) progression and its treatment have not been reported. Several public datasets were used to look into the possible link between the amount of palmitoylated Nrf2 and the progression and its outcome of GC in patients. The palmitoylated Nrf2 levels in tumoral and peritumoral tissues from GC patients were also evaluated. Both loss-of-function and gain-of-function via transgenic experiments were performed to study the effects of palmitoylated Nrf2 on carcinogenesis and the pharmacological function of 2-bromopalmitate (2-BP) on the suppression of GC progression in vitro and in vitro. We discovered that Nrf2 was palmitoylated in the cytoplasmic domain, and this lipid posttranslational modification causes Nrf2 stabilization by inhibiting ubiquitination, delaying Nrf2 destruction via the proteasome and boosting nuclear translocation. Importantly, we also identify palmitoyltransferase zinc finger DHHC-type palmitoyltransferase 2 (DHHC2) as the primary acetyltransferase required for the palmitoylated Nrf2 and indicate that the suppression of Nrf2 palmitoylation via 2-bromopalmitate (2-BP), or the knockdown of DHHC2, promotes anti-cancer immunity in vitro and in mice model-bearing xenografts. Of note, based on the antineoplastic mechanism of 2-BP, a novel anti-tumor drug delivery system ground 2-BP and oxaliplatin (OXA) dual-loading gold nanorods (GNRs) with tumor cell membrane coating biomimetic nanoparticles (CM@GNRs-BO) was established. In situ photothermal therapy is done using near-infrared (NIR) laser irradiation to help release high-temperature-triggered drugs from the CM@GNRs-BO reservoir when needed. This is done to achieve photothermal/chemical synergistic therapy. Our findings show the influence and linkage of palmitoylated Nrf2 with tumoral and peritumoral tissues in GC patients, the underlying mechanism of palmitoylated Nrf2 in GC progression, and novel possible techniques for addressing Nrf2-associated immune evasion in cancer growth. Furthermore, the bionic nanomedicine developed by us has the characteristics of dual drugs delivery, homologous tumor targeting, and photothermal and chemical synergistic therapy, and is expected to become a potential platform for cancer treatment.

ZnO-ZnS Heterostructure as a Potent Photocatalyst in the Preparation of Some Substituted Chromenes and Remarkable Antigastrointestinal Cancer Activity.

The nanosized hybrid material ZnO-ZnS was synthesized using the well-known sol-gel method, as a simple and environmentally friendly procedure. The material was then characterized using various techniques including FESEM, TEM, UV-vis, DRS, EDS, XRD, and FT-IR. The characterization studies revealed the generation of ZnO-ZnS nanoparticles with a mean size of around 25 nm. Moreover, DRS analysis provided a band gap of 3.05 eV for this nanomaterial. The photocatalytic properties of the ZnO-ZnS heterojunction was investigated in the synthesis of some substituted chromenes under mild reaction conditions. The results showed that the prepared nanophotocatalyst exhibits significantly higher activity compared to its individual components (ZnO and ZnS) and provides 73-87% yield with 0.01 g of ZnO-ZnS after 30 min. In addition, the nanophotocatalyst demonstrated a high reusability in the desired condensation reaction. The enhanced photocatalytic activity of ZnO-ZnS can be attributed to the slower recombination of the electron-hole pairs in this semiconductor material. The reactive species OH•, •O2-, and h+ are believed to play important roles in the photocatalytic system. Furthermore, cellular toxicity of ZnO-ZnS nanoparticles was evaluated on HCT-116 human gastrointestinal cancer cell line by MTT assay. The results proved a distinct reduction of cell viability, proofing cytotoxicity of nanoparticles on the cancer cells. This study highlights the potential of the nanoparticles against gastrointestinal cancer.

Single-cell analysis of gastric signet ring cell carcinoma reveals cytological and immune microenvironment features.

Gastric signet ring cell carcinoma (GSRC) is a special subtype of gastric cancer (GC) associated with poor prognosis, but an in-depth and systematic study of GSRC is lacking. Here, we perform single-cell RNA sequencing to assess GC samples. We identify signet ring cell carcinoma (SRCC) cells. Microseminoprotein-beta (MSMB) can be used as a marker gene to guide the identification of moderately/poorly differentiated adenocarcinoma and signet ring cell carcinoma (SRCC). The upregulated differentially expressed genes in SRCC cells are mainly enriched in abnormally activated cancer-related signalling pathways and immune response signalling pathways. SRCC cells are also significantly enriched in mitogen-activated protein kinase and oestrogen signalling pathways, which can interact and promote each other in a positive feedback loop. SRCC cells are shown to have lower cell adhesion and higher immune evasion capabilities as well as an immunosuppressive microenvironment, which may be closely associated with the relatively poor prognosis of GSRC. In summary, GSRC exhibits unique cytological characteristics and a unique immune microenvironment, which may be advantageous for accurate diagnosis and treatment.

OASL knockdown inhibits the progression of stomach adenocarcinoma by regulating the mTORC1 signaling pathway.

The present study investigated the effects of 2'-5' oligoadenylate synthetase-like (OASL) on the biological functions of stomach adenocarcinoma (STAD) cells and tumor formation in nude mice. The differential expression levels of OASL in the different cancer types from TCGA dataset were analyzed using gene expression profiling interactive analysis. Overall survival and the receiver operating characteristic were analyzed using the KM plotter and R, respectively. Furthermore, OASL expression and its effects on the biological functions of STAD cells were detected. The possible upstream transcription factors of OASL were predicted using JASPAR. The downstream signaling pathways of OASL were analyzed using GSEA. Tumor formation experiments were performed to evaluate the effect of OASL on tumor formation in nude mice. The results showed that OASL was highly expressed in STAD tissues and cell lines. OASL knockdown markedly inhibited cell viability, proliferation, migration, and invasion and accelerated STAD cell apoptosis. Conversely, OASL overexpression had the opposite effect on STAD cells. JASPAR analysis revealed that STAT1 is an upstream transcription factor of OASL. Furthermore, GSEA showed that OASL activated the mTORC1 signaling pathway in STAD. The protein expression levels of p-mTOR and p-RPS6KB1 were suppressed by OASL knockdown and promoted by OASL overexpression. The mTOR inhibitor, rapamycin, markedly reversed the effect of OASL overexpression on STAD cells. Additionally, OASL promoted tumor formation and increased tumor weight and volume in vivo. In conclusion, OASL knockdown suppressed the proliferation, migration, invasion, and tumor formation of STAD cells by inhibiting the mTOR signaling pathway.

Loss of cancer-associated fibroblast-derived exosomal DACT3-AS1 promotes malignant transformation and ferroptosis-mediated oxaliplatin resistance in gastric cancer.

AIMS: Long non-coding RNAs (lncRNAs), as one of the components of exosomes derived from cancer-associated fibroblasts (CAFs), exhibit a crucial role in the pathogenesis and chemoresistance of gastric cancer (GC). Herein, we investigated the role and mechanism of a novel lncRNA disheveled binding antagonist of beta catenin3 antisense1 (DACT3-AS1) and its involvement in GC. METHODS: DACT3-AS1 was identified by RNA-sequencing and verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The functional role of DACT3-AS1 in GC was evaluated using in vitro and in vivo experiments including Transwell assay, 5-Ethynyl-2'-deoxyuridine (EdU) assay, immunoblotting, and xenograft tumor mouse model. Dual-luciferase reporter assay was performed to assess the association between genes. RESULTS: DACT3-AS1 was downregulated and involved in poor prognosis of patients with GC. The results from both in vitro and in vivo experiments showed that DACT3-AS1 suppressed cell proliferation, migration, and invasion through targeting miR-181a-5p/sirtuin 1 (SIRT1) axis. Additionally, DACT3-AS1 was transmitted from CAFs to GC cells mainly via exosomes. Exosomal DACT3-AS1 alleviated xenograft tumor growth. DACT3-AS1 conferred sensitivity of cancer cells to oxaliplatin through SIRT1-mediated ferroptosis both in vitro and in vivo. CONCLUSIONS: CAFs-derived exosomal DACT3-AS1 is a suppressive regulator in malignant transformation and oxaliplatin resistance. DACT3-AS1 could be used for diagnosis and treatment of GC.

AKAP8L enhances the stemness and chemoresistance of gastric cancer cells by stabilizing SCD1 mRNA.

Gastric cancer (GC) remains the third leading cause of cancer-related deaths. Chemoresistance is the major determinant of GC treatment failure. To explore the molecular mechanisms of GC chemoresistance, mass spectrometry was performed to detect the genes altered in expression between chemoresistant and chemosensitive GC. PRKA kinase anchor protein 8L (AKAP-8L) was identified as one of the top upregulated genes in chemoresistant GC tissues. Moreover, the higher AKAP-8L expression was associated with the lower survival rate in GC patients. Overexpression of AKAP-8L enhanced the GC cell stemness and chemoresistance of oxaliplatin in vivo and in vitro. AKAP-8L deficiency obtained the opposite results. Mechanistically, AKAP-8L interacted with Stearoyl-CoA desaturase 1 (SCD1) mRNA and IGF2BP1 protein, and regulated SCD1 mRNA stability via IGF2BP1-dependent manner. SCD1 played a critical role in mediating the function of AKAP-8L in GC cell stemness and chemoresistance. Clinically, AKAP-8L and SCD1 protein levels was positively associated with human GC chemoresistance. Taken together, our results demonstrated that AKAP-8L facilitates GC chemoresistance via regulating SCD1-mediated stemness of GC cells. AKAP8L may represent a novel therapeutic target to overcome GC chemoresistance.

Oligoadenylate synthetases-like is a prognostic biomarker and therapeutic target in pancreatic ductal adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) is fatal cancer that causes death. Early metastasis, resistance to chemotherapy, and lack of treatment contribute to a poor prognosis. Therefore, finding new therapeutic targets and biomarkers is a particularly urgent need to improve the survival of PDAC patients. Oligoadenylate synthetases-like (OASL), an antiviral enzyme produced by interferon (IFN), has been found to be associated with the occurrence and development of multiple cancers. However, its role in PDAC has been less well-studied. The value of OASL in PDAC was evaluated by bioinformatics and in vitro experiments. Methods: The expression of OASL was evaluated using the Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA) online websites. The survival time was also calculated by GEPIA. The correlation between OASL messenger RNA (mRNA) expression and immune infiltration was analyzed by the Tumor Immune Estimation Resource (TIMER) database. Clinical characteristics were revealed by The Cancer Genome Atlas (TCGA) data. A nomogram and forest plot were constructed based on univariate and multivariate Cox regression. Cell experiments [western blot assays, 3-(4,5-dimethylathiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, transwell assays, flow cytometry assays] were used to verify the value of OASL in PDAC cells (Panc-1, Mia paca-2, and Aspc-1). Results: A higher expression of OASL was observed in PDAC (P<0.05). Patients with increased expression of OASL had worse overall survival (OS; P<0.05) and disease-specific survival (DSS; P<0.05). The expression of OASL was correlated with T stage (P=0.030) and N stage (P=0.004), radiation therapy (P=0.013), primary therapy outcome (P<0.001), residual tumor (P=0.028), and tumor location (P=0.004) by univariate analysis, which also confirmed that OASL was an independent prognostic factor. Moreover, OASL expression was positively associated with neutrophils. In vitro experiments indicated that knockdown of OASL inhibited cell viability and invasion while increasing apoptosis rate. Conclusions: High expression of OASL is associated with poor prognosis. Targeting OASL delays PDAC tumor progression in vitro. We highlight that OASL is a novel prognostic biomarker and therapeutic target of PDAC.

A Clinical Study on the Treatment of Children's Short Stature with Auxiliary Comprehensive Management Combined with Growth Patch.

OBJECTIVE: To explore the clinical effect of auxiliary comprehensive management combined with growth patch in the treatment of childhood idiopathic short stature (ISS). METHODS: From September 2017 to December 2019, 120 children with ISS who met the selection criteria were collected. Random number table method divided them into 2 groups: one group was given auxiliary comprehensive management and recorded as the routine group (n = 60), and the other group was given auxiliary comprehensive management and combined growth patch treatment and recorded as the combination group (n = 60). The course of treatment was 12 months. The effects of the two methods on children's height, bone age, body weight, and insulin-like growth factor (IGF)-1 and IGF-binding protein (IGFBP)-3 levels were compared. RESULTS: There was no statistical difference between the two groups in baseline height, genetic height, baseline bone age, baseline body weight, and body weight before and after treatment (P > 0.05). After treatment, the heights of the two groups were higher than before for the same group, the height growth values and predicted adult height of the combination group were higher than those of the routine group, and the predicted adult height of the combination group was higher than the genetic height of the same group (P < 0.001). There was no statistical difference in IGF-1 and IGFBP-3 levels before treatment between the two groups (P > 0.05). The levels of IGF-1 and IGFBP-3 after treatment in the two groups were higher than those in the same group before treatment, and the combination group was higher than that in the routine group (P < 0.05). CONCLUSION: On the basis of auxiliary comprehensive management, combined with growth patch for the treatment of children with ISS, it can effectively increase the height of the children, improve the levels of serum IGF-1 and IGFBP-3, and have significant clinical effects, which is beneficial to the healthy growth of the children.

Application Research of Individualized Conditional Reprogramming System to Guide Treatment of Gastric Cancer.

BACKGROUND: Gastric cancer (GC) is one of the most common causes of malignant tumors in the world. Due to the high heterogeneity of GC and lack of specificity of available chemotherapy regimens, these tumors are prone to resistance, recurrence, and metastasis. Here, we formulated an individualized chemotherapy regimen for GC using a modified individual conditional reprogramming (i-CR) system. We established a primary tumor cell bank of GC cells and completed drug screening in order to realize individualized and accurate GC treatment. METHODS: We collected specimens from 93 surgical or gastroscopy GC cases and established a primary tumor cell bank using the i-CR system and PDX models. We also completed in vitro culture and drug sensitivity screening of the GC cells using the i-CR system. Whole-exome sequencing (WES) of the i-CR cells was performed using P0 and P5. We then chose targeted chemotherapy drugs based on the i-CR system results. RESULTS: Of the 72 cases that were collected from surgical specimens, 26 cases were successfully cultured with i-CR system, and of the 21 cases collected from gastroscopy specimens, seven were successfully cultured. Among these, 20 cases of the PDX model were established. SRC ± G3 had the highest culture success rate. The i-CR cells of P0 and P5 appeared to be highly conserved. According to drug sensitivity screening, we examined the predictive value of responses of GC patients to chemotherapeutic agents, especially in neoadjuvant patients. CONCLUSION: The i-CR system does not only represent the growth characteristics of tumors in vivo, but also provides support for clinical drug use. Drug susceptibility results were relatively consistent with clinical efficacy.

RUNX2 as a promising therapeutic target for malignant tumors.

The transcription factor runt-related protein 2 (RUNX2) has an important impact on the transformation of bone marrow mesenchymal stem cells to osteoblasts. Further studies have shown that RUNX2 plays a key role in the invasion and metastasis of cancers. RUNX2 is a "key" molecule in the regulatory network comprised of multiple signaling pathways upstream and its target downstream molecules. Due to the complex regulatory mechanisms of RUNX2, the specific mechanism underlying the occurrence, development and prognosis of malignant tumors has not been fully understood. Currently, RUNX2 as a promising therapeutic target for cancers has become a research hotspot. Herein, we reviewed the current literature on the modulatory functions and mechanisms of RUNX2 in the development of malignant tumors, aiming to explore its potential clinical application in the diagnosis, prognosis and treatment of tumors.

[Clinical research on recombinant human Ad-p53 injection combined with cisplatin in treatment of malignant pleural effusion induced by lung cancer].

BACKGROUND AND OBJECTIVE: p53 gene is one of cancer suppressor genes and its mutation and deletion induces almost all human cancers. This study was to evaluate the clinical efficacy and toxicity of recombinant human Ad-p53 injection (rAd-p53) combined with cisplatin in treatment of malignant pleural effusion induced by lung cancer. METHODS: A total of 35 cases of malignant pleural effusion were randomly divided into the combined group (n=17) and the single-agent group (n=18). On the basis of systemic treatment (vinorelbine 25 mg/m2, Days 1-8, every 3 weeks), the combined group were given intracavitary administration of rAd-p53 (1x1012 VP) and cisplatin (40 mg/m2) once a week for 4 weeks. The single-agent group were given the same intracavitary administration as the combined group but without rAd-p53 therapy. RESULTS: The total effective rates in the combined group and the single-agent group were 82.35% and 50.00% (P<0.05), respectively. The total modification rates in the combined group and the single-agent group were 64.70% and 33.33% (P<0.05), respectively. The toxicities in the two groups were fever, stethalgia, nausea/vomiting and leukopenia. The toxic reaction in combined group was mainly self-limited fever (P<0.05), which disappeared automatically after 36 h. CONCLUSIONS: rAd-p53 and cisplatin is safe and effective for malignant pleural effusion induced by lung cancer. It is worthy of application in clinical treatment.