Comprehensive analysis of glycoprotein VI-mediated platelet activation signaling pathway for predicting pan-cancer survival and response to anti-PD-1 immunotherapy.

Platelets play a vital role in cancer and immunity. However, few comprehensive studies have been conducted on the role of platelet-related signaling pathways in various cancers and their responses to immune checkpoint blockade (ICB) therapy. In the present study, we focused on the glycoprotein VI-mediated platelet activation (GMPA) signaling pathway and comprehensively evaluated its roles in 19 types of cancers listed in The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Cox regression and meta-analyses showed that for all 19 types of cancers, patients with high GMPA scores tended to have a good prognosis. Furthermore, the GMPA signature score could serve as an independent prognostic factor for patients with skin cutaneous melanoma (SKCM). The GMPA signature was linked to tumor immunity in all 19 types of cancers, and was correlated with SKCM tumor histology. Compared to other signature scores, the GMPA signature scores for on-treatment samples were more robust predictors of the response to anti-PD-1 blockade in metastatic melanoma. Moreover, the GMPA signature scores were significantly negatively correlated with EMMPRIN (CD147) and positively correlated with CD40LG expression at the transcriptomic level in most cancer patient samples from the TCGA cohort and on-treatment samples from anti-PD1 therapy cohorts. The results of this study provide an important theoretical basis for the use of GMPA signatures, as well as GPVI-EMMPRIN and GPVI-CD40LG pathways, to predict the responses of cancer patients to various types of ICB therapy.

Chemo-free maintenance therapy in adult T-cell acute lymphoblastic leukemia: A case report and literature review.

Maintenance therapy in adult T-cell acute lymphoblastic leukemia (T-ALL) is the longest phase but with limited option. The classic drugs used in the maintenance phase such as 6-mercaptopurine, methotrexate, corticosteroid and vincristine have potentially serious toxicities. Optimizing therapy in the modern age, chemo-free maintenance therapy regimens for patients with T-ALL may dramatically improve the maintenance therapeutic landscape. We report here the combination of Anti-programmed cell death protein 1 antibody and histone deacetylase inhibitor as chemo-free maintenance treatment in a T-ALL patient with literature review, thus providing a unique perspective in addition to valuable information which may inform novel therapeutic approaches.

Changing causes of death in persons with haematological cancers 1975-2016.

Causes of death in persons with haematological cancers include the index cancer, a new cancer or a seemingly unrelated cause such as cardio-vascular disease. These causes are complex and sometimes confounded. We analyzed trends in cause of death in 683,333 persons with an index haematological cancer diagnosed in 1975-2016 reported in the Surveillance, Epidemiology and End Results dataset. Non-cancer deaths were described using standardized mortality ratios. The index cancer was the predominant cause of death amongst persons with plasma cell myeloma, acute lymphoblastic leukaemia and acute myeloid leukaemia. Non-cancer death was the major cause of death in persons with chronic lymphocytic leukaemia, Hodgkin lymphoma and chronic myeloid leukaemia, mostly from cardio-vascular diseases. The greatest relative decrease in index-cancer deaths was amongst persons with Hodgkin lymphoma, chronic myeloid leukaemia and chronic lymphocytic leukaemia, where the proportion of non-cancer deaths increased substantially. Changing distribution of causes of death across haematological cancers reflects substantial progress in some cancers and suggests strategies to improve the survival of persons with haematological cancers in the future.

Performance of common genetic variants in risk prediction for colorectal cancer in Chinese: A two-stage and multicenter study.

The efficacy of susceptible variants derived from genome-wide association studies (GWAs) optimizing discriminatory accuracy of colorectal cancer (CRC) in Chinese remains unclear. In the present validation study, we assessed 75 recently identified variants from GWAs. A risk predictive model combining 19 variants using the least absolute shrinkage and selection operator (LASSO) statistics offered certain clinical advantages. This model demonstrated an area under the receiver operating characteristic (AUC) of 0.61 during training analysis and yielded robust AUCs from 0.59 to 0.61 during validation analysis in three independent centers. The individuals carrying the highest quartile of risk score revealed over 2-fold risks of CRC (ranging from 2.12 to 2.90) compared with those who presented the lowest quartile of risk score. This genetic model offered the possibility of partitioning risk within the average risk population, which might serve as a first step toward developing individualized CRC prevention strategies in China.

Immunohistochemical analysis of HNF4A and ß-catenin expression to predict low-grade dysplasia in the colitis-neoplastic sequence.

Animal studies indicated that P1 promoter-driven hepatocyte nuclear factor 4 alpha (HFN4A) prevents carcinogenesis in colitis. But the function of total HNF4A protein has not been fully investigated, and it was assumed to be involved in the colitis-neoplastic sequence. The aim of this study was to determine the clinical value of total P1-/P2-driven HNF4A combined with ß-catenin in the colitis-neoplastic sequence. A total of 69 samples, including 4 normal colon tissues, 16 sporadic colorectal cancer (CRC) tissues, 35 inflammatory bowel disease (IBD) tissues, and 14 IBD-associated low-grade dysplasia tissues, were collected to assess P1-/P2-driven HNF4A and ß-catenin expressions by immunohistochemical assay. In addition, a colonic epithelial cell line Caco2 with stable P1-/P2-driven HNF4A knockdown was constructed. ß-Catenin expression and skeleton structure were determined in the transfected cells by western blot analysis and immunofluorescence assay respectively. Increased expression of nuclear P1-/P2-driven HNF4A was observed in the colitis-associated colorectal neoplasm and sporadic CRC samples, compared with that in colitis samples. The parallel alterations between cytoplasmic ß-catenin and nuclear P1-/P2-driven HNF4A were also verified. Silencing of P1-/P2-driven HNF4A expression in Caco2 cells decreased ß-catenin expression and F-actin formation. Our results confirmed the elevated expressions of nuclear P1-/P2-driven HNF4A and cytoplasmic ß-catenin in the colitis-neoplastic sequence, and both of them may be used as potential biomarkers to predict low-grade dysplasia.

Pharmacological Ascorbate Suppresses Growth of Gastric Cancer Cells with GLUT1 Overexpression and Enhances the Efficacy of Oxaliplatin Through Redox Modulation.

Rationale: The antitumor activity of high-dose ascorbate has been re-evaluated recently, but the mechanism underlying cell-specific sensitivity to ascorbate has not yet been clarified. Methods: The effects of high-dose ascorbate on gastric cancer were assessed using cancer cell lines with high and low expression of GLUT1 via flow cytometry and colony formation assays in vitro and patient-derived xenografts in vivo. Results: In this study, we demonstrated that gastric cancer cells with high GLUT1 expression were more sensitive to ascorbate treatment than cells with low GLUT1 expression. GLUT1 knockdown significantly reversed the therapeutic effects of pharmacological ascorbate, while enforced expression of GLUT1 enhanced the sensitivity to ascorbate treatment. The efficacy of pharmacological ascorbate administration in mice bearing cell line-based and patient-derived xenografts was influenced by GLUT1 protein levels. Mechanistically, ascorbate depleted intracellular glutathione, generated oxidative stress and induced DNA damage. The combination of pharmacological ascorbate with genotoxic agents, including oxaliplatin and irinotecan, synergistically inhibited gastric tumor growth in mouse models. Conclusions: The current study showed that GLUT1 expression was inversely correlated with sensitivity of gastric cancer cells to pharmacological ascorbate and suggested that GLUT1 expression in gastric cancer may serve as a marker for sensitivity to pharmacological ascorbate.

SPP1 rs4754 and its epistatic interactions with SPARC polymorphisms in gastric cancer susceptibility.

The matricellular glycoprotein products of the SPP1 and SPARC genes play critical roles in many aggressive tumor phenotypes including gastric cancer. We sought to test whether the polymorphisms of these two genes, individually or jointly, influence gastric cancer susceptibility. Nine potentially functional, tagging single nucleotide polymorphisms (tagSNPs) of SPP1 and SPARC were selected and detected using the Kompetitive Allele Specific PCR method in 301 gastric cancer cases and 1441 healthy control subjects. We found that the genotype frequencies of SPP1 rs4754 in gastric cancer were significantly different from those in controls. The rs4754 TT genotype conferred an increased risk of gastric cancer, with unadjusted and adjusted ORs ranging from 1.75 to 1.95 (all P<0.05). The assessment of the effect modifications of sex and age on the genetic effects also confirmed the statistically significant association of the rs4754 TT genotype with increased gastric cancer risk. Epistatic interactions were found between SPP1 rs4754 and SPARC rs1054204, rs3210714 and rs3549 (all P values for interaction<0.05). During the assessment of the epistatic effects between pairs of interacting factors, increased gastric cancer risk was observed in the combined presence of the SPP1 rs4754 TT genotype and the common genotypes of interacting SPARC SNPs, with ORs ranging from 3.94 to 4.41. When the genetic influence of SPP1 rs4754 TT was excluded, the genetic effects of the SPARC rs1054204, rs3210714 and rs3549 common genotypes on gastric cancer susceptibility switched from being risky to beneficial. These data reveal an association between the SPP1 rs4754 polymorphism and altered risk of gastric cancer and highlight an important role of the epistatic effects of SPP rs4754 with SPARC polymorphisms in gastric carcinogenesis. Additional functional experiments and independent large-scale studies, especially in other ethnic populations, are needed to confirm our results.

Long noncoding RNA XIST expedites metastasis and modulates epithelial-mesenchymal transition in colorectal cancer.

Tumor progression and metastasis is the main cause of death in colorectal cancer (CRC). Long noncoding RNAs (lncRNAs) are critical regulators in various diseases including human cancer. In this study, we found that lncRNA XIST was overexpressed in CRC cell lines and tissues. High expression of lncRNA XIST was associated with adverse overall survival in CRC patients. Knockdown of lncRNA XIST remarkably inhibited CRC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and CRC stem cell formation in vitro as well as tumor growth and metastasis in vivo. Further study indicated that knockdown of lncRNA XIST markedly increased the expression of microRNA-200b-3p (miR-200b-3p) that has been found to be downregulated in CRC tissues and cell lines, and luciferase activity assay indicated that lncRNA XIST could bind directly with miR-200b-3p. Moreover, knockdown of lncRNA XIST significantly reduced the expression of ZEB1, which was the direct target of miR-200b-3p, and the tumor suppressive effects caused by knockdown of lncRNA XIST could be rescued by re-expression of ZEB1 in CRC cells. Overall, our study demonstrated how lncRNA XIST regulates CRC progression and metastasis by competing for miR-200b-3p to modulate the expression of ZEB1. lncRNA XIST may be used as a biomarker to predict prognosis in CRC patients.

Melatonin enhances sensitivity to fluorouracil in oesophageal squamous cell carcinoma through inhibition of Erk and Akt pathway.

Oesophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-associated death in the world and novel therapeutic alternatives are urgently warranted. In this study, we investigated the anti-tumour activity and underlying mechanisms of melatonin, an indoleamine compound secreted by the pineal gland as well as naturally occurring plant products, in ESCC cells and revealed that melatonin inhibited proliferation, migration, invasion and induced mitochondria-dependent apoptosis of ESCC cells in vitro and suppressed tumour growth in the subcutaneous mice model in vivo. Furthermore, after treatment with melatonin, the expressions of pMEK, pErk, pGSK3ß and pAkt were significantly suppressed. In contrast, treatment of the conventional chemotherapeutic drug fluorouracil (5-Fu) resulted in activation of Erk and Akt, which could be reversed by co-treatment with melatonin. Importantly, melatonin effectively enhanced cytotoxicity of 5-Fu to ESCC in vitro and in vivo. Together, these results suggested that inhibition of Erk and Akt pathway by melatonin have an important role in sensitization of ESCC cells to 5-Fu. Combined 5-Fu and melatonin treatment may be appreciated as a useful approach for ESCC therapy that warrants further investigation.

Long non-coding RNA XIST regulates gastric cancer progression by acting as a molecular sponge of miR-101 to modulate EZH2 expression.

BACKGROUND: Long non-coding RNAs (lncRNAs) have emerged as critical regulators of tumor progression. However, the role and molecular mechanism of lncRNA XIST in gastric cancer is still unknown. METHODS: Real-time PCR analysis was performed to measure the expression levels of lncRNA XIST in gastric cancer tissues and cell lines, the correlation between lncRNA XIST expression and clinicopathological characteristics and prognosis was analyzed in gastric cancer patients. The biological function of lncRNA XIST on gastric cancer cells were determined both in vitro and in vivo. The regulating relationship between lncRNA XIST and miR-101 was investigated in gastric cancer cells. RESULTS: lncRNA XIST was significantly up-regulated in gastric cancer tissues and cell lines. Overexpression of lncRNA XIST was markedly associated with larger tumor size, lymph node invasion, distant metastasis and TNM stage in gastric cancer patients. Functionally, knockdown of lncRNA XIST exerted tumor-suppressive effects by inhibiting cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. Furthermore, an inverse relationship between lncRNA XIST and miR-101 was found. Polycomb group protein enhancer of zeste homolog 2 (EZH2), a direct target of miR-101, could mediated the biological effects that lncRNA XIST exerted. CONCLUSIONS: lncRNA XIST is up-regulated and is associated with aggressive tumor phenotypes and patient survival in gastric cancer, and the newly identified lncRNA XIST/miR-101/EZH2 axis could be a potential biomarkers or therapeutic targets for gastric cancer patients.

Inhibition of the NF-κB pathway by nafamostat mesilate suppresses colorectal cancer growth and metastasis.

Nafamostat mesilate is an anti-inflammatory drug that is usually used to treat pancreatitis. Recent studies show that it can suppress pancreatic cancer via inhibition of the nuclear factor κB (NF-κB) pathway. However, whether it has anti-tumor activity in some other cancer, including colorectal cancer (CRC), has not been investigated and remained unclear. Here, our study showed that nafamostat mesilate abrogated the constitutive NF-κB activation in CRC cells, which is mediated through inhibition of phosphorylation of IκBα and nuclear translocation of p65. Also, we found that nafamostat mesilate inhibited phosphorylation of Erk in CRC cells. Consistently, our study demonstrated that nafamostat mesilate inhibited the CRC cell proliferation, invasion and migration and induced mitochondria-dependent apoptosis. Furthermore, nafamostat mesilate could reverse oxaliplatin induced NF-κB and Erk activation in CRC cells, and enhance the sensitivity of CRC cells to oxaliplatin. Nafamostat mesilate combined with oxaliplatin repressed subcutaneous tumor growth and hepatic metastasis in vivo. Overall, our data suggest that nafamostat mesilate, a relatively non-toxic drug that targets NF-κB and Erk, may, in combination with oxaliplatin, represent a novel therapeutic strategy for CRC treatment.

Melatonin overcomes gemcitabine resistance in pancreatic ductal adenocarcinoma by abrogating nuclear factor-κB activation.

Constitutive activation and gemcitabine induction of nuclear factor-κB (NF-κB) contribute to the aggressive behavior and chemotherapeutic resistance of pancreatic ductal adenocarcinoma (PDAC). Thus, targeting the NF-κB pathway has proven an insurmountable challenge for PDAC therapy. In this study, we investigated whether the inhibition of NF-κB signaling pathway by melatonin might lead to tumor suppression and overcome gemcitabine resistance in pancreatic tumors. Our results showed that melatonin inhibited activities of NF-κB by suppressing IκBα phosphorylation and decreased the expression of NF-κB response genes in MiaPaCa-2, AsPc-1, Panc-28 cells and gemcitabine resistance MiaPaCa-2/GR cells. Moreover, melatonin not only inhibited cell proliferation and invasion in a receptor-independent manner, but also enhanced gemcitabine cytotoxicity at pharmacologic concentrations in these PDAC cells. In vivo, the mice treated with both agents experienced a larger reduction in tumor burden than the single drug-treated groups in an orthotopic xenograft mouse model. Taken together, these results indicate that melatonin inhibits proliferation and invasion of PDAC cells and overcomes gemcitabine resistance of pancreatic tumors through NF-κB inhibition. Our findings therefore provide novel preclinical knowledge about melatonin inhibition of NF-κB in PDAC and suggest that melatonin should be investigated clinically, alone or in combination with gemcitabine for PDAC treatment.

microRNA-217 inhibits tumor progression and metastasis by downregulating EZH2 and predicts favorable prognosis in gastric cancer.

microRNA-217 (miR-217) is frequently dysregulated in cancer. Here, we report that miR-217 levels were lower in tumor tissue compared with the adjacent normal tissue. Low levels of miR-217 were associated with aggressive tumor phenotypes and poor overall survival in gastric cancer patients. The ectopic expression of miR-217 inhibited cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo, whereas knockdown of endogenous miR-217 increased cell proliferation and invasion. Further experiments revealed that Polycomb group protein enhancer of zeste homolog 2 (EZH2) was a direct target of miR-217 in gastric cancer cells. Knockdown of EZH2 mimicked the tumor-suppressive effects of miR-217 in gastric cancer cells, whereas the reintroduction of EZH2 abolished its effects. Taken together, these results demonstrated that miR-217 may be used as a prognostic marker, and the newly identified miR-217-EZH2 axis may be a potential target in the development of therapeutic strategies for gastric cancer patients.