Nanoformulation of Apolipoprotein E3-Tagged Liposomal Nanoparticles for the co-Delivery of KRAS-siRNA and Gemcitabine for Pancreatic Cancer Treatment.

PURPOSE: KRAS is the most frequently mutated gene in human cancers, and ~ 90% of pancreatic cancers exhibit KRAS mutations. Despite the well-known role of KRAS in malignancies, directly inhibiting KRAS is challenging. METHODS: In this study, we successfully synthesized apolipoprotein E3-based liposomes for the co-delivery of gemcitabine (GEM) and a small interfering RNA targeting KRAS (KRAS-siRNA) to improve the efficacy of pancreatic cancer treatment. RESULTS: Apolipoprotein E3 self-assembly on the liposome surface led to a substantial increase in its internalization in PANC1 human pancreatic cancer cells. KRAS-siRNA led to downregulated KRAS protein expression and KRAS-dependent carcinogenic pathways, resulting in the inhibition of cell proliferation, cell cycle arrest, increased apoptosis, and suppression of tumor progression. The combination of KRAS-siRNA and GEM induced a synergistic improvement in cell apoptosis and significantly lower cell viability compared with single-agent therapy. The low IC50 value of A3-SGLP might be attributed to potentiation of the anticancer effect of GEM by siRNA-mediated silencing of KRAS mutations, thereby inducing synergistic effects on cancer cells. CONCLUSION: A3-SGLP led to a marked decrease in the overall tumor burden and did not show any signs of toxicity. Therefore, the combination of KRAS-siRNA and GEM holds great potential for the treatment of pancreatic cancer.

Long Non-Coding RNA LINC01089 Enhances the Development of Gastric Cancer by Sponging miR-145-5p to Mediate SOX9 Expression.

BACKGROUND: Long non-coding RNAs (lncRNAs) have potential regulatory effects in oncogenesis. Previous studies showed that several lncRNAs could participate in the progression of gastric cancer (GC). However, the specific biological mechanisms in GC are still unclear. We analyzed an lncRNA microarray of GC and selected LINC01089 for study. METHODS: LINC01089 expression in GC was tested by qRT-PCR. GC cell proliferation was assessed using CCK-8 and EdU assays. Cell invasion was assessed using the Transwell assay. A dual-luciferase reporter gene assay and bioinformatics assay were performed to detect potential targets of LINC01089. Additionally, RNA immunoprecipitation and Western blot assays were performed to clarify their interactions and roles in the regulation of GC progression. RESULTS: High LINC01089 expression was observed in GC cells. LINC01089 overexpression notably expedited cell migration, proliferation, and invasion. LINC01089 positively regulated SOX9 expression by competitively binding to microRNA (miR-145-5p). CONCLUSION: LINC01089 competitively binds to miR-145-5p to mediate SOX9 expression. LINC01089 may participate in the progression of GC.

Advantages of Restoring miR-205-3p Expression for Better Prognosis of Gastric Cancer via Prevention of Epithelial-mesenchymal Transition.

PURPOSE: miR-205 is a tumor suppressor and plays an important role in tumor invasiveness. However, the role of miR-205 in human gastric cancer (GC) epithelial-mesenchymal transition (EMT) remains unclear. The aim of this study was to investigate the molecular mechanism of miR-205 in the regulation of EMT in GC invasion. MATERIALS AND METHODS: Quantitative polymerase chain reaction (qPCR) was used to detect the expression of miR-205 in GC. Further, the correlation between the pathological parameters and prognosis of GC was statistically analyzed. A transwell model was used to evaluate the effect of miR-205-3p on the invasion and migration of GC cells. qPCR, western blotting, and luciferase assay were performed to analyze the relationship and target effects between miR-205-3p and the expression of zinc finger electron box binding homologous box 1 (ZEB1) and 2 (ZEB2). RESULTS: We found that the levels of miR-205-3p were significantly lower (P<0.05) in GC tissues than in matched normal tissues. Additionally, the expression of miR-205-3p was related to the tumor invasion depth, lymph node metastasis, lymph node invasion, and tumor, node, metastasis stage. Patients with lower miR-205-3p expression levels in the tumors had a poorer prognosis. The in vitro assays indicated that miR-205-3p could affect the invasion ability and EMT of GC cells by targeting the expression of both ZEB1 and ZEB2. CONCLUSIONS: miR-205-3p promotes GC progression and affects the prognosis of patients by targeting both ZEB1 and ZEB2 to directly influence EMT.

APOC3rs2854116, PNPLA3rs738409, and TM6SF2rs58542926 polymorphisms might influence predisposition of NAFLD: A meta-analysis.

It is plausible that apolipoprotein C3 (APOC3), patatin-like phospholipase domain containing 3 (PNPLA3), and transmembrane 6 superfamily member 2 (TM6SF2) polymorphisms may affect predisposition of nonalcoholic fatty liver disease (NAFLD), but the results of so far published studies remain controversial. The authors conducted this meta-analysis to clarify relationships between APOC3/PNPLA3/TM6SF2 polymorphisms and predisposition of NAFLD by pooling the findings of eligible studies. A comprehensive search of PubMed, Embase, Web of Science, and CNKI was endorsed by the authors to identify already published studies. Forty-nine studies were found to be eligible for meta-analyses. The pooled meta-analyses results showed that genotypic frequencies of APOC3 rs2854116, PNPLA3 rs738409, and TM6SF2 rs58542926 polymorphisms among patients and controls differed significantly. Moreover, genotypic frequencies of PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms among patients and controls from both Caucasians and Asians also differed significantly. But However, no such differences in genotypic frequencies were observed for the APOC3 rs2854117 polymorphism. This meta-analysis suggested that APOC3 rs2854116, PNPLA3 rs738409, and TM6SF2 rs58542926 polymorphisms might affect predisposition of NAFLD.

Associations of polymorphisms in interleukins with susceptibility to breast cancer: Evidence from a meta-analysis.

BACKGROUND: Associations between polymorphisms in interleukins and breast cancer (BC) were already investigated by many studies, yet with controversial findings. The aim of this meta-analysis was to better clarify associations between polymorphisms in interleukins and BC by combing the results of all relevant articles. METHODS: Eligible articles were searched from Pubmed, Embase, Web of Science and CNKI. We used Review Manager to combine the results of eligible studies. RESULTS: Fifty-seven studies were included in this meta-analysis. We found that IL-6 rs1800796 (dominant comparison: OR = 0.70, 95% CI 0.53-0.92), IL-8 rs4073 (dominant comparison: OR = 0.74, 95% CI 0.61-0.89; over-dominant comparison: OR = 1.16, 95% CI 1.05-1.29; allele comparison: OR = 0.82, 95% CI 0.69-0.89), IL-10 rs1800896 (recessive comparison: OR = 1.28, 95% CI 1.12-1.47) and IL-18 rs1946518 (dominant comparison: OR = 0.80, 95% CI 0.65-0.97; allele comparison: OR = 0.74, 95% CI 0.59-0.93) polymorphisms were all significantly associated with BC in overall combined analyses. In subgroup analyses, we noticed that IL-6 rs1800796, IL-8 rs4073, IL-10 rs1800896, IL-18 rs1946518 and rs187238 polymorphisms were all significantly associated with susceptibility to BC in East Asians from China. CONCLUSIONS: Collectively, this meta-analysis demonstrated that IL-6 rs1800796, IL-8 rs4073, IL-10 rs1800896, IL-18 rs1946518 and rs187238 polymorphisms may confer susceptibility to BC for East Asians from China.

Tumor-associated macrophages induce invasion and poor prognosis in human gastric cancer in a cyclooxygenase-2/MMP9-dependent manner.

Cyclooxygenase-2 (COX2) and tumor-associated macrophages (TAMs) are associated with invasion, angiogenesis, and poor prognosis in many human cancers. However, the role of TAMs in human gastric cancer (GC) remains elusive. In the present study, we first measured COX2 expression and TAM infiltration in human GC tissues using double immunohistochemical staining. Then, we indirectly cocultured M2-polarized macrophages derived from human THP-1 cells with GC cells as an in vitro model. Transwell assays, siRNA transfection, treatment with a COX2 inhibitor and Western blotting were used to investigate the relationship among TAMs, invasion and COX2 expression as well as the underlying molecular mechanism. Double IHC staining showed that TAMs were aggregated near GC tumor nests and had high COX2 expression; moreover, the number of TAMs that infiltrated the tumor nest was correlated with the depth of invasion, COX2 expression and poor prognosis in human GC. In an in vitro assay, after treatment with phorbol myristate acetate (PMA), the THP-1 cells differentiated into M2 macrophages and induced COX2/MMP9-dependent invasiveness in GC cells. Pretreatment of GC cells with COX2 siRNA or a COX2 inhibitor (Celecoxib) can negate these promoting effects. The results of this study and those of our previous studies indicate that coculture with M2-polarized macrophages can induce the COX2-dependent release of matrix metalloproteinase-9 (MMP9), which subsequently increases the invasiveness of GC cells. Our data may provide a basis for targeting TAMs or for polarizing TAMs through immune regulation to halt GC progression, which could soon become a nonsurgical treatment for human gastric cancer.

Long non-coding RNA SNHG1 functions as a competitive endogenous RNA to regulate PDCD4 expression by sponging miR-195-5p in hepatocellular carcinoma.

Long non-coding RNA (lncRNA) potentially regulates tumorigenesis. LncRNA small nucleolar RNA host gene 1 (SNHG1) expression remains high in hepatocellular carcinoma cells; however, its biological mechanism in hepatocellular carcinoma remains unknown. In this study, SNHG1 expression in hepatocellular carcinoma cells was detected by qRT-PCR. Proliferative and migratory potentials of hepatocellular carcinoma cells were determined by CCK-8 and Transwell assay, respectively. Then, the nude mice model of xenograft was employed to verify the effect of SNHG1 on tumor formation in vivo. We identified the potential target of SNHG1 through bioinformatics and dual-luciferase reporter gene. Furthermore, Western blot and RIP assay was used for clarifying their interaction and functions in regulating the development of hepatocellular carcinoma. Our results indicated a high expression of SNHG1 in hepatocellular carcinoma cells. Downregulation of SNHG1 inhibited proliferative and migratory potentials of hepatocellular carcinoma cells in vitro and in vivo. Moreover, the expression of programmed cell death 4 (PDCD4) was positively regulated by SNHG1 through competing with miR-195-5p. These results indicated that SNHG1 participated in the development of hepatocellular carcinoma as a ceRNA to competitively bind to miR-195-5p and thus mediate PDCD4 expression.

Programmed death-ligand 1 monoclonal antibody-linked immunoliposomes for synergistic efficacy of miR-130a and oxaliplatin in gastric cancers.

Aim: PD-L1 monoclonal antibody-conjugated miR-130a/oxaliplatin-loaded immunoliposomes were constructed for enhanced therapeutic efficacy against gastric cancer. Materials & methods: The in vitro antitumor efficacy of the immunoliposomes was evaluated by cell viability, cell invasion, cell apoptosis and western blot analysis and in vivo antitumor efficacy was evaluated in a HGC27-bearing tumor xenograft model. Results: The inhibitory role of miR-130a was demonstrated in HGC27 cells by the downregulation of RAB5A and FOCL1 signaling pathways. Consequently, PD-miOXNP exhibited the strongest anticancer activity in vitro compared with any other formulation. PD-miOXNP showed a significantly higher anticancer efficacy in HGC27 tumors with reduced Ki67+ cells and increased TUNEL+ cells for mice group. Conclusion: PD-L1 monoclonal antibody-conjugated immunoliposomes have immense potential to be applied as a next-generation nanomedicine for PD-L1-positive gastric cancers.

Lnc-GIHCG promotes cell proliferation and migration in gastric cancer through miR- 1281 adsorption.

BACKGROUND: Long noncoding RNAs (lncRNAs) are from the family of noncoding RNAs. Existing studies have shown that lncRNAs are involved in many biological processes and are strongly related to the occurrence and development of tumors. Recent studies have indicated that lncRNA GIHCG participates in the progression of many cancers by adjusting cell proliferation and migration. Gastric cancer (GC) is a prevalent malignant tumor that arises from gastric epithelium. This study mainly explored the influence of GIHCG on GC and its underlying mechanism. METHODS: GIHCG expression was detected in GC through quantitative real-time polymerase chain reaction while the relationship of GIHCG with miR-1281 and miR-1281 with TLE1 was verified using dual luciferase reporter gene assay. The influence of GIHCG, miR-1281 and TLE1 on cell function was verified using cell counting Kit-8 (CCK-8) and Transwell experiment. RESULTS: In GC, GIHCG was significantly overexpressed and significantly increased cell proliferation and migration, with the possible mechanism of upregulatingTLE1 expression through adsorption of miR-1281. CONCLUSION: Taken together, we revealed the role of GIHCG/miR-1281/TLE1 in GC and provided a new perspective.

Overexpression of Myosin Phosphatase Target Subunit 1 (MYPT1) Inhibits Tumor Progression and Metastasis of Gastric Cancer.

BACKGROUND Myosin phosphatase target subunit 1 (MYPT1) serves as a subgroup of myosin phosphatases, and is frequently low-expressed in human cancers. However, little is known about the effects of MYPT1 in gastric cancer (GC). MATERIAL AND METHODS In our study, MYPT1 expression was detected by quantitative real-time reverse transcription PCR (qRT-PCR) in GC tissues, different advanced pathological stages of GC tissues, and preoperative and postoperative patients. Kaplan-Meier analysis was used to measure the overall survival of GC patients. MYPT1 expression was analyzed by qRT-PCR and Western blot assays in GES-1 cells and GC cells. Cell proliferation, cycle, and migration and invasion abilities were detected by CCK-8, flow cytometry, and Transwell assays. E-cadherin, TIMP-2, MMP-2, MMP-9 RhoA, and p-RhoA expressions were assessed by qRT-PCR and Western blot assays in treated SNU-5 cells. RESULTS Our results indicated that MYPT1 was down-regulated in GC tissues and cells, and is related to clinical stages and overall survival of GC. Functional research demonstrated that overexpression of MYPT1 can inhibit cell proliferation, cell cycle progression, and migration and invasion of GC cells. Many studies on mechanisms reported that overexpression of MYPT1 dramatically improved the expression levels of cell cycle-related genes (Cyclin D1 and c-myc), significantly increased epithelial marker (E-cadherin) expression, and decreased invasion-associated genes (TIMP-2 and MMP-2) expressions in SNU-5 cells. In addition, we found that MYPT1 suppressed RhoA phosphorylation. CONCLUSIONS We verified that MYPT1 inhibits GC cell proliferation and metastasis by regulating RhoA phosphorylation.

Multicolor fluorescent switches in gel systems controlled by alkoxyl chain and solvent.

Two simple molecules, 1 and 2 with D-pi-A structure and alkoxyl groups, respectively, were designed and synthesized. Both compounds can gelatinize THF-water and DMSO. And compound 2 forms gel in acetone by ultrasonic stimulus. Interestingly, these gels exhibit aggregation-induced emission (AIE) during the sol-gel phase transformation. Moreover, the molecular self-assembled and photophysical properties can be controlled by the number of the alkoxyl chains and the type of the solvents. For example, 1 has an identical packing model and fluorescent colour in THF-water and DMSO gels. Contrarily, the self-assembly of molecule 2 strongly depends on the solvent. Furthermore, the gel phases of 2 formed in three solvents possess different fluorescent colours. Such as, THF-water gel emits yellow fluorescence, acetone gel has orange emission and red fluorescence appears in DMSO.

Aggregation-induced blue shift of fluorescence emission due to suppression of TICT in a phenothiazine-based organogel.

A new D-pi-A type gelator based on a phenothiazine derivative, which can gel cyclohexane, hexane, and ethanol/water under ultrasound treatment, has been synthesized. Because such gelators can act as twisted intermolecular charge transfer (TICT) probes, their emission in solution can be tuned by varying the polarity of the solvents. It is notable that an unusual aggregation-induced blue shift of the emission has been detected on account of the suppression of TICT in the gel phase.