Long-term outcomes of esophageal and gastric cancer patients with cardiovascular and metabolic diseases: A two-center propensity score-matched cohort study.

Background and Objectives: An increased risk of cardiovascular and metabolic diseases (CVMDs) among patients with cancer suggests a potential link between CVMD and cancer. The impact of CVMD on the survival time of patients with esophageal and gastric cancer remains unknown. We aimed to determine the incidence of CVMD and its impact on the longterm outcomes in esophageal and gastric cancer patients. Methods: A total of 2074 cancer patients were enrolled from January 1, 2007 to December 31, 2017 in two hospitals, including 1205 cases of esophageal cancer and 869 cases of gastric cancer, who were followed up for a median of 79.8 and 79.3 months, respectively. Survival time was analyzed using the Kaplan-Meier method before and after propensity score matching. Results: The incidence of CVMD in patients with esophageal and gastric cancer was 34.1% (411/1205) and 34.3% (298/869), respectively. The effects of hypertension, diabetes, and stroke on the long-term survival of esophageal and gastric cancer patients were not significant (all P > 0.05). The survival time was significantly longer in esophageal cancer patients without ischemic heart disease than in patients with ischemic heart disease, both before matching (36.5 vs. 29.1 months, P = 0.027) and after matching (37.4 vs. 27.9 months, P = 0.011). The survival time in gastric cancer patients without ischemic heart disease was significantly longer than in patients with ischemic heart disease, both before (28.4 vs.17.5 months, P = 0.032) and after matching (29.5 vs.17.5 months, P = 0.02). Conclusion: The survival time of esophageal and gastric cancer patients with ischemic heart disease was significantly reduced compared to that of esophageal and gastric cancer patients without ischemic heart disease.

Computational study on novel natural compound inhibitor targeting IDH1_R132H.

Isocitrate dehydrogenases (IDH) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. IDH1 mutation has been reported in various tumors especially Cholangiocarcinoma, while the IDH1_R132H is reported to be the most common mutation of IDH1. IDH1_R132H inhibitors are effective anti-cancer drugs and have shown significant therapeutic effects in clinical. In this study, two novel natural compounds were identified to combine respectively with IDH1_R132H with a stronger binding force with conductive to interaction energy. They also showed low toxicity potential. Molecular dynamics simulation analysis demonstrated that the candidate ligands-IDH1_R132H complexes is stable in natural circumstances with favorable potential energy. Thus, Styraxlignolide F and Tremulacin were screened as promising IDH1_R132H inhibitors. We provide a solid foundation for the design and development of IDH1_R132H targeted drugs.

Selected by bioinformatics and molecular docking analysis, Dhea and 2-14,15-Eg are effective against cholangiocarcinoma.

OBJECT: To identify novel targets for the diagnosis, treatment and prognosis of cholangiocarcinoma, we screen ideal lead compounds and preclinical drug candidates with MYC inhibitory effect from the ZINC database, and verify the therapeutic effect of Dhea and 2-14,15-Eg on cholangiocarcinoma. METHODS: The gene expression profiles of GSE132305, GSE89749, and GSE45001 were obtained respectively from the Gene Expression Omnibus database. The DEGs were identified by comparing the gene expression profiles of cholangiocarcinoma and normal tissues. GO, KEGG analysis and PPI network analyses were performed. LibDock, ADME and toxicity prediction, molecular docking and molecular dynamics simulations were used to identify potential inhibitors of MYC. Moreover, in vitro, MTT assay, colony-forming assay, the scratch assay and Western blotting were performed to verify the therapeutic effect of Dhea and 2-14,15-Eg. RESULTS: PPI network analysis showed that ALB, MYC, APOB, IGF1 and KNG1 were hub genes, of which MYC was mainly studied in this study. A battery of computer-aided virtual techniques showed that Dhea and 2-14,15-Eg have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6, as well as could exist stably in natural circumstances. In vitro assays showed that Dhea and 2-14,15-Eg inhibited cholangiocarcinoma cellular viability, proliferation, and migration inhibiting expression of MYC. CONCLUSION: This study suggested that Dhea and 2-14,15-Eg were novel potential inhibitors of MYC targeting, as well as are a promising drug in dealing with cholangiocarcinoma and have a perspective application.

MicroRNA-613 induces the sensitivity of gastric cancer cells to cisplatin through targeting SOX9 expression.

Increasing evidences have suggested that deregulated miRNAs may involve in drug chemoresistance in a lot of human cancers. However, the role of miR-613 in drug chemoresistance of GC cell is still unknown. The expression of miR-613 and Sex-determining region Y (SRY)-box 9 (SOX9) in GC tissues and cell lines was detected by using qRT-PCR. Cell migration and viability were measured by the wound healing assay and CCK-8 assays. Western blot and dual-luciferase reporter were done to identify the target gene of miR-613. We showed that miR-613 expression was downregulated in GC tissues and cell lines. Ectopic expression of miR-613 increased the sensitivity of GC cells to cisplatin. Overexpression of miR-613 suppressed GC cell proliferation, cycle and migration. In addition, we identified SOX9 was a direct target gene of miR-613 in GC cell. We showed that SOX9 expression was upregulated in gastric cancer samples. Moreover, the expression of SOX9 was negatively correlated with miR-613 expression in GC tissues. Furthermore, elevated expression of miR-613 increased the sensitivity of GC cells to cisplatin and suppressed GC cell proliferation and migration by targeting SOX9. These data suggested that miR-613 might function as a chemoresistant suppressor in GC.

miR-144-3p Induces Cell Cycle Arrest and Apoptosis in Pancreatic Cancer Cells by Targeting Proline-Rich Protein 11 Expression via the Mitogen-Activated Protein Kinase Signaling Pathway.

microRNAs (miRNAs) have been proved to be involved in many events of tumor development and progression, including cell proliferation, cell apoptosis, and cell cycle arrest. However, the potential role of miR-144-3p in pancreatic cancer (PC) remains elusive. In this study, we demonstrated that miR-144-3p was decreased in PC tissues and PANC-1 cells, whereas proline-rich protein 11 (PRR11) was remarkably increased. miR-144-3p mimics were discovered to inhibit cell proliferation by arresting cells at the S-phase of the cell cycle, and inducing cell apoptosis in PANC-1 cells. The effects of miR-144-3p on cell proliferation and cell apoptosis were reversed after treatment with the miR-144-3p inhibitor. Furthermore, a luciferase activity assay indicated that miR-144-3p directly targeted PRR11 3'-UTR. Moreover, transfection with miR-144-3p mimics inhibited the expression of PRR11. miR-144-3p mimics also upregulated the expression of p-JNK and p-p38, whereas they downregulated the expression of p-ERK. The effects of miR-144-3p on mitogen-activated protein kinase pathway proteins were reversed by the miR-144-3p inhibitor. PRR11 overexpression attenuated the effect of miR-144-3p mimics on cell apoptosis and cell cycle arrest. The expression of caspase-3 was decreased by enhanced PRR11. In summary, our findings indicated that miR-144-3p induced cell cycle arrest and apoptosis in PC by targeting PRR11. Therefore, the targeting of miR-144-3p could serve as a potential therapeutic strategy for the treatment of PC.

TXNIP overexpression suppresses proliferation and induces apoptosis in SMMC7221 cells through ROS generation and MAPK pathway activation.

Thioredoxin binding protein (thioredoxin-interacting protein, TXNIP), known as vitamin D3 increase protein 1, has been identified as a tumor suppressor in various cancers such as pancreatic, breast, lung and thyroid cancer. However, the role of TXNIP in hepatocellular carcinoma cell proliferation and apoptosis remains unknown. In this study, we first used qRT-PCR, western blotting and immunohistochemistry to compare the expression of TXNIP between hepatocellular carcinoma tissues and tumor-adjacent normal liver tissues. In vitro, we explored the role of TXNIP in hepatocellular carcinoma progression via transfection of the pcDNA-3.1-TXNIP plasmid into SMMC7221 cells. Our results showed that the expression of TXNIP was significantly decreased in hepatocellular carcinoma tissues. Moreover, TXNIP over-expression inhibited hepatocellular carcinoma cell proliferation and induced apoptosis by triggering mitochondrial-mediated ROS generation and activating MAPK pathways. This study provides insight into the molecular mechanisms of TXNIP overexpression in liver cancer cell survival and apoptosis and indicated that TXNIP may be a novel promising agent for liver cancer treatment.

NOR1 promotes hepatocellular carcinoma cell proliferation and migration through modulating the Notch signaling pathway.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Previous studies have reported that the oxidored-nitro domain containing protein 1 (NOR1) is a novel tumor suppressor in several tumors. Recent evidence suggests that NOR1 is strongly expressed in HCC cells. However, its role and mechanism in HCC are unclear. In the current study, Western blot and qPCR detected strong NOR1 mRNA and protein expression in HepG2 and Hep3B cells. After transfection with NOR1 siRNA or pcDNA3.1-myc-his-NOR1, the proliferation and migration of HepG2 and Hep3B cells were analyzed in vitro. HepG2 or Hep3B cells overexpressing NOR1 showed an increased proliferation and migration, whereas siRNA-mediated silencing of NOR1 showed the opposite effect. Furthermore, NOR1 activated the Notch signaling pathway, indicated by increased levels of Notch1, NICD, Hes1, and Hey1 in protein. Importantly, the Notch inhibitor DAPT downregulated Notch activation and further enhanced siNOR1-induced reduction of cell proliferation and migration in HepG2 and Hep3B cells, whereas DAPT reversed the effect of NOR1 overexpression on cell proliferation and migration. In conclusion, these results indicate that NOR1 may be involved in the progression of HCC and thus may be a potential target for the treatment of liver cancer.

Let-7a mimic attenuates CCL18 induced breast cancer cell metastasis through Lin 28 pathway.

BACKGROUND: MicroRNAs are believed to influence breast cancer cell tumorgenicity by interacting with the production of tumor associated macrophages. At this stage, this hypothesis lacks sufficient empirical evidence. Our study is an investigation of the effects of let-7a on the function of human breast cancer cell lines that had undergone chemokine ligand 18 (CCL18) stimulation. METHODS: Two breast cancer cell lines MDA-MB-231 and MCF-7 were transfected with let-7a mimics with or without CCL18 simulation. The expression level of let-7a was evaluated with qRT-PCR. Our study examined cell proliferation, migration and cell cycles following let-7a treatment. The predicted target of let-7a was identified and confirmed in vitro by a dual luciferase reporter system. The associations between let-7a, CCL18 and target gene expression were evaluated using RT-PCR and the Western blotting method. RESULTS: The downregulated expression level of let-7a was observed in both breast cancer cell lines. When compared to the control and CCL18 stimulation groups, cell proliferation and migration in MDA-MB-231 and MCF-7 cells were significantly inhibited by let-7a. Furthermore, the cell cycle was dramatically blocked at the G2/M phase. The luciferase reporter identified Lin28 as the direct binding target of let-7a in both breast cancer cell lines. CONCLUSION: Upregulation of let-7a carries the potential to reverse CCL18 induced cell proliferation and migration alteration in breast cancer cells by regulating Lin28 expression. Our results provided evidence which suggests the use of let-7a as a therapeutic agent in the treatment of breast cancer.