CEMIP, acting as a scaffold protein for bridging GRAF1 and MIB1, promotes colorectal cancer metastasis via activating CDC42/MAPK pathway.

Metastasis is the leading cause of treatment failure and tumor-related death in colorectal cancer (CRC). Our previous studies report that CEMIP functionally promotes CRC metastasis and is closely related to poor outcomes. However, the molecular network of CEMIP promoting CRC metastasis is still not fully understood. In the current study, we identify CEMIP interacting with GRAF1, and the combination of high-CEMIP and low-GRAF1 predicts poor survival of patients. Mechanistically, we elucidate that CEMIP interacts with the SH3 domain of GRAF1 through the 295-819aa domain, and negatively regulates the stability of GRAF1. Moreover, we identify MIB1 to be an E3 ubiquitin ligase for GRAF1. Importantly, we uncover that CEMIP acts as a scaffold protein in bridging MIB1 and GRAF1, which is critical to GRAF1 degradation and CEMIP-mediated CRC metastasis. Furthermore, we found that CEMIP activates CDC42/MAPK pathway-regulated EMT by enhancing the degradation of GRAF1, which is indispensable to CEMIP-mediated migration and invasion of CRC cells. Subsequently, we prove that CDC42 inhibitor suppresses CEMIP-mediated CRC metastasis in vitro and in vivo. Collectively, our results reveal that CEMIP promotes CRC metastasis through GRAF1/CDC42/MAPK pathway-regulated EMT, and suggest that CDC42 inhibitor could be a novel therapeutic strategy for CEMIP-mediated CRC metastasis.

KIAA1199 promotes oxaliplatin resistance and epithelial mesenchymal transition of colorectal cancer via protein O-GlcNAcylation.

Oxaliplatin is a commonly used platinum drug for colorectal cancer (CRC). However, the treatment of CRC by oxaliplatin usually fails because of drug resistance, which results in a huge challenge in the therapy of CRC. Elucidation of molecular mechanisms may help to overcome oxaliplatin resistance of CRC. In our study, we revealed that KIAA1199 can promote oxaliplatin resistance of CRC. Mechanistically, KIAA1199 prevents oxaliplatin mediated apoptosis via up-regulated PARP1 derived from reduced endoplasmic reticulum stress induced by protein O-GlcNAcylation. In the meantime, KIAA1199 can also trigger epithelial mesenchymal transition by stabilizing SNAI1 protein via O-GlcNAcylation. Therefore, KIAA1199 has great potential to be a novel biomarker, therapeutic target for oxaliplatin resistance and metastasis of CRC.

Tumor CEMIP drives immune evasion of colorectal cancer via MHC-I internalization and degradation.

BACKGROUND: Loss of major histocompatibility complex class I (MHC-I) in tumor cells limits the use of immune checkpoint blockade (ICB) in colorectal cancer. Nevertheless, the regulatory mechanism of MHC-I downregulation in tumor cells has not been fully elucidated. Overexpression of CEMIP in tumor tissues is associated with a poor prognosis in colorectal cancer. Here, in this research, we aim to address the role of CEMIP in mediating MHC-I expression in tumor cells and investigate the underlying regulatory mechanisms. METHOD: Protein levels were analyzed by western blotting. Flow cytometry analysis was used to examine immune cells. Protein-protein interactions were investigated by co-immunoprecipitation and proximity ligation assays. The intracellular trafficking of MHC-I was revealed by an immunofluorescent technique. In addition, the effect of CEMIP on tumor growth and the antitumor efficacy of targeting CEMIP in combination with ICB therapy were evaluated in murine models of colorectal cancer. RESULTS: We reported that CEMIP specifically downregulated the expression of MHC-I on the surface of murine and human colon cancer cells, hindering the cytotoxicity of CD8+ T cells. We also demonstrated that CEMIP restricted CD8+ T-cell antitumor activities both in vitro and in vivo due to impaired MHC-I-mediated antigen presentation. Correspondingly, the combination of CEMIP inhibition and ICB impeded tumor growth and enhanced therapeutic efficacy. Mechanistically, CEMIP acted as an adaptor for the interaction betweenMHC-I and clathrin, which drove MHC-I internalization via clathrin-dependent endocytosis. Furthermore, CEMIP anchored internalized MHC-I to lysosomes for degradation, disrupting the recycling of MHC-I to the cell surface. CONCLUSION: Overall, our study unveils a novel regulatory mechanism of MHC-I on tumor cell surfaces by CEMIP-mediated internalization and degradation. Furthermore, targeting CEMIP provides an effective strategy for colorectal cancer immunotherapy.

KIAA1199 drives immune suppression to promote colorectal cancer liver metastasis by modulating neutrophil infiltration.

BACKGROUND AND AIMS: Metastasis is the primary cause of cancer mortality, and colorectal cancer (CRC) frequently metastasizes to the liver. Our previous studies demonstrated the critical role of KIAA1199 in tumor invasion and metastasis in CRC. In the present study, we described an immune regulatory effect of KIAA1199 that creates a permissive environment for metastasis. APPROACH AND RESULTS: Flow cytometry was used to examine the effects of KIAA1199 on the infiltration of tumor immune cells. Neutrophils and T cells were isolated, stimulated, and/or cultured for in vitro function assays. In the patients with CRC, high expression levels of KIAA1199 were associated with an increased neutrophil infiltration into the liver. This result was further validated in mouse metastasis models. The increased influx of neutrophils contributed to the KIAA1199-driven CRC liver metastasis. Mechanistically, KIAA1199 activated the TGFß signaling pathway by interacting with the TGFBR1/2 to stimulate CXCL1 and CXCL3 production, thereby driving the aggregation of immunosuppressive neutrophils. Genetic blockade or pharmacologic inhibition of KIAA1199 restored tumor immune infiltration, impeded tumor progression, and potentiated response to immune checkpoint blockade (ICB). CONCLUSIONS: These findings indicated that KIAA1199 could facilitate the liver infiltration of immunosuppressive neutrophils via the TGFß-chemokine (C-X-C motif) ligand (CXCL)3/1-CXCR2 axis, which might be clinically targeted for the treatment of hepatic metastasis.

CEMIP, a novel adaptor protein of OGT, promotes colorectal cancer metastasis through glutamine metabolic reprogramming via reciprocal regulation of ß-catenin.

Metastasis is the leading cause of colorectal cancer (CRC)-induced death. However, the underlying molecular mechanisms of CRC metastasis are poorly understood. Metabolic reprogramming is an intrinsic feature of cancer, which have complicated effects on cancer metastasis. Here, we find that a novel metastasis-related protein, cell migration-inducing and hyaluronan-binding protein (CEMIP), can act as a novel adaptor protein of O-GlcNAc transferase (OGT) to promote CRC metastasis through glutamine metabolic reprogramming. Mechanistically, CEMIP interacts with OGT and ß-catenin, which leads to elevated O-GlcNAcylation of ß-catenin and enhanced ß-catenin nuclear translocation from cytomembrane. Furthermore, accumulated ß-catenin in nucleus enhances the transcription of CEMIP to reciprocally regulate ß-catenin and contributes to over-expression of glutaminase 1 and glutamine transporters (SLC1A5 and SLC38A2). Combinational inhibition of CEMIP and glutamine metabolism could dramatically attenuate the metastasis of CRC in vivo. Collectively, this study reveals the importance of glutamine metabolic reprogramming in CEMIP-induced CRC metastasis, indicating the great potential of CEMIP and glutamine metabolism for CRC metastasis prevention.

Prognostic Factors of Survival of Advanced Liver Cancer Patients Treated With Palliative Radiotherapy: A Retrospective Study.

AIMS: Survival benefit of liver cancer patients who undergo palliative radiotherapy varies from person to person. The present study aims to identify indicators of survival of advanced liver cancer patients receiving palliative radiotherapy. PATIENTS AND METHODS: One hundred and fifty-nine patients treated with palliative radiotherapy for advanced liver cancer were retrospectively assessed. Of the 159 patients, 103 patients were included for prediction model construction in training phase, while other 56 patients were analyzed for external validation in validation phase. In model training phase, clinical characteristics of included patients were evaluated by Kaplan-Meier curves and log-rank test. Thereafter, multivariable Cox analysis was taken to further identify characteristics with potential for prediction. In validation phase, a separate dataset including 56 patients was used for external validation. Harrell's C-index and calibration curve were used for model evaluation. Nomograms were plotted based on the model of multivariable Cox analysis. RESULTS: Thirty-one characteristics of patients were investigated in model training phase. Based on the results of Kaplan-Meier plots and log-rank tests, 6 factors were considered statistically significant. On multivariable Cox regression analysis, bone metastasis (HR = 1.781, P = 0.026), portal vein tumor thrombus (HR = 2.078, P = 0.015), alpha-fetoprotein (HR = 2.098, P = 0.007), and radiation dose (HR = 0.535, P = 0.023) show significant potential to predict the survival of advanced liver cancer patients treated with palliative radiotherapy. Moreover, nomograms predicting median overall survival, 1- and 2-year survival probability were plotted. The Harrell's C-index of the predictive model is 0.709(95%CI, 0.649-0.769) and 0.735 (95%CI, 0.666-0.804) for training model and validation model respectively. Calibration curves of the 1- and 2-year overall survival of the predictive model indicate that the predicted probabilities of OS are very close to the actual observed outcomes both in training and validation phase. CONCLUSION: Bone metastasis, portal vein tumor thrombus, alpha-fetoprotein and radiation dose are independent prognostic factors for the survival of advanced liver cancer patients treated with palliative radiotherapy.

Meta-analysis and indirect treatment comparison of modified FOLFIRINOX and gemcitabine plus nab-paclitaxel as first-line chemotherapy in advanced pancreatic cancer.

BACKGROUND: Modified FOLFIRINOX and gemcitabine plus nab-paclitaxel (GEM-NAB) have been recommended as first-line therapies for advanced pancreatic cancer (PC). Due to the lack of evidence to directly compare them, we conducted this network meta-analysis to indirectly compare the effectiveness and toxicity of modified FOLFIRINOX and GEM-NAB. METHODS: The eligible retrospective studies on treatments related to modified FOLFIRINOX and GEM-NAB up to 4 April 2020 were searched and assessed. We used the frequentist model to analyze the survival and toxicity data between different treatments. Pooled analysis for overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and events of toxicity were analyzed in this study. RESULTS: Twenty-two studies were involved in this network meta-analysis. The comparisons on OS and PFS showed that modified FOLFIRINOX and GEM-NAB had similar treatment efficacy (OS: 1.13; 95% CI: 0.78-1.63; PFS: HR: 1.19; 95% CI: 0.85-1.67). GEM-NAB was more effective than modified FOLFIRINOX based on the result of ORR (RR: 1.43; 95% CI: 1.04-1.96). Moreover, our analysis showed a similar toxicity profile between modified FOLFIRINOX and GEM-NAB. CONCLUSIONS: The current evidence showed that modified FOLFIRINOX and GEM-NAB were similar in survival and toxicity. Many factors should be considered for in the formulation of optimal treatment, and our meta-analysis could provide some guidance to treatment selection in the first-line setting for advanced PC.

Comparison of first line chemotherapy regimens for advanced soft tissue sarcoma: a network meta-analysis.

The best first line chemotherapy regimen for advanced soft tissue sarcoma (ASTS) remains inconclusive. Here, we aimed to find the best first line chemotherapy regimen by performing a network meta-analysis. Regimens were compared in terms of overall survival (OS), overall response rate(ORR), progression free survival (PFS), and toxicity. Twenty-eight eligible trials with a total of 6928 patients were included. EC (epirubicin + cisplatin) was considered as the better regimen for advanced STS with probability of 61.9% in terms of OS. However, this regimen only have been evaluated in a single small trial and tend to have more hematological toxicities than doxorubicin. No regimen was superior to doxorubicin with significant statistical difference in terms of PFS and ORR, even aldoxorubicin behaved better than doxorubicin in the network analysis. Collectively, doxorubicin still can be selected preferentially for the first line chemotherapy for patients.

Volatile Organic Compounds in Human Exhaled Breath to Diagnose Gastrointestinal Cancer: A Meta-Analysis.

INTRODUCTION: Human exhaled volatile organic compounds (VOCs) are being extensively studied for the purposes of noninvasive cancer diagnoses. This article was primarily to assess the feasibility of utilizing exhaled VOCs analysis for gastrointestinal cancer (GIC) diagnosis. METHODS: PRISMA-based system searches were conducted for related studies of exhaled VOCs in GIC diagnosis based on predetermined criteria. Relevant articles on colorectal cancer and gastroesophageal cancer were summarized, and meta analysis was performed on articles providing sensitivity and specificity data. RESULTS: From 2,227 articles, 14 were found to meet inclusion criteria, six of which were on colorectal cancer (CRC) and eight on Gastroesophageal cancer(GEC). Five articles could provide specific data of sensitivity and specificity in GEC, which were used for meta-analysis. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated based on the combination of these data, and were 85.0% [95% confidence interval (CI): 79.0%-90.0%], 89.0% (95%CI: 86.0%-91.0%), 41.30 (21.56-79.10), and 0.93, respectively. CONCLUSION: VOCs can distinguish gastrointestinal cancers from other gastrointestinal diseases, opening up a new avenue for the diagnosis and identification of gastrointestinal cancers, and the analysis of VOCs in exhaled breath has potential clinical application in screening. VOCs are promising tumor biomarkers for GIC diagnosis. Furthermore, limitations like the heterogeneity of diagnostic VOCs between studies should be minded.

Effect of anthracyclines/ifosfamide-based adjuvant chemotherapy for soft tissue sarcoma: a conventional and network Meta-analysis.

The objective of this study is to assess the effect of anthracyclines/ifosfamide-based adjuvant chemotherapy for soft tissue sarcoma (STS) and provide a relative ranking of regimens for STS. We pooled the hazard ratios of overall survival (OS) and relapse free survival (RFS) by conventional meta-analysis to appraise whether adjuvant chemotherapy benefits STS and performed a network meta-analysis using a Bayesian model to establish the relative ranking of regimens. Nine studies were included in our meta-analysis. The pooled hazard ratios were 0.68 (95%CI: 0.53-0.86) and 0.65 (95%CI: 0.52-0.83) for OS and RFS, respectively. Doxorubicin was indicated as best regimen to benefit OS (probability: 30.2%), while cyclophosphamide + vincristine + doxorubicin + dactinomycin was indicated as the best regimen for RFS (probability: 37.1%). This meta-analysis confirms the positive effect of anthracyclines/ifosfamide-based adjuvant chemotherapy in STS for both OS and RFS.

SNORA71A Promotes Colorectal Cancer Cell Proliferation, Migration, and Invasion.

Small nucleolar RNAs (snoRNAs) play a crucial role during colorectal cancer (CRC) development. The study of SNORA71A is few, and its role in CRC is unknown. This study focused on screening abnormal snoRNAs in CRC and exploring the role of key snoRNA in CRC. The expression pattern of snoRNAs in 3 CRC and 3 normal colon tissues was detected via small RNA sequencing. The six candidate snoRNAs were identified by quantitative PCR (qPCR). Subsequently, the expression level of SNORA71A was further verified through the Cancer Genome Atlas (TCGA) data analysis and qPCR. The CCK8 and transwell assays were used to detect the functional role of SNORA71A in CRC cells. The integrated analysis of snoRNA expression profile indicated that a total 107 snoRNAs were significantly differentially expressed (DE) in CRC tissues compared with normal tissues, including 45 upregulated and 62 downregulated snoRNAs. Bioinformatics analysis revealed that the DE snoRNAs were mainly implicated in "detection of chemical stimulus involved in sensory perception of smell" and "sensory perception of smell" in the biological process. The DE snoRNAs were preferentially enriched in "olfactory transduction" and "glycosphingolipid biosynthesis-ganglio series pathway." The expression of SNORA71A was upregulated in CRC tissues and cells. SNORA71A expression showed statistically significant correlations with TNM stage (P = 0.0196) and lymph node metastasis (P = 0.0189) and can serve as biomarkers for CRC. Importantly, SNORA71A significantly facilitated the CRC cell proliferation, migration, and invasion. Our findings indicate that SNORA71A screened by sequencing acted as an oncogene and promoted proliferation, migration, and invasion ability of CRC cells.

Detection of volatile organic compounds in exhaled breath to screen lung cancer: a systematic review.

To evaluate the clinical value of volatile organic compounds (VOCs) in exhaled breath for lung cancer (LC) screening, a systematic review was performed. Systematic search for studies about exhaled VOCs for LC screening was conducted according to PRISMA. Thirty eight studies with 4873 participants met the criteria for inclusion in this systematic review. Generally speaking, the results suggest that exhaled VOCs have potential to screen LC and more studies are needed in the future.

Volatile metabonomic profiling in urine to detect novel biomarkers for B-cell non-Hodgkin's lymphoma.

To date, there have been a limited number of useful biomarkers for the screening and monitoring of B-cell non-Hodgkin's lymphoma (B-NHL), which leads to the impetus to discover novel biomarkers for the disease. In the present study, gas chromatography-mass spectrometry (GC-MS) combined with head-space solid-phase micro-extraction (HS-SPME) was employed to analyze the volatile metabolites in the urine samples of 131 subjects. The subjects were divided into 4 main groups: Aggressive B-NHL, indolent B-NHL, benign lymphatic diseases patients and healthy volunteers. The differences of the concentrations of the potential biomarkers among the groups were assessed by non-parametric Wilcoxon's test. The ability of the potential biomarkers to discriminate between the four aforementioned groups was evaluated by receiver operating characteristic curves (ROC). The present study indicated that 4-heptanone, 2-methylpyrazine, 2-methylbutanal, 2,6-dimethyl-7-octen-2-ol and decanoic acid may serve as potential biomarkers for B-NHL. The area under the curve (AUC) values of single potential biomarker ranged from 0.634 to 0.901. The diagnostic models established with combined biomarkers exhibited higher diagnostic values (AUC, 0.824-0.968) compared with the models established with single biomarkers. The present study indicated that urinary volatile metabolites might be potential biomarkers for screening and monitoring of B-NHL.

Diagnosis and Classification of 17 Diseases from 1404 Subjects via Pattern Analysis of Exhaled Molecules.

We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others. Cluster analysis showed a reasonable classification power of diseases from the same categories. The effect of confounding clinical and environmental factors on the performance of the nanoarray did not significantly alter the obtained results. The diagnosis and classification power of the nanoarray was also validated by an independent analytical technique, i.e., gas chromatography linked with mass spectrometry. This analysis found that 13 exhaled chemical species, called volatile organic compounds, are associated with certain diseases, and the composition of this assembly of volatile organic compounds differs from one disease to another. Overall, these findings could contribute to one of the most important criteria for successful health intervention in the modern era, viz. easy-to-use, inexpensive (affordable), and miniaturized tools that could also be used for personalized screening, diagnosis, and follow-up of a number of diseases, which can clearly be extended by further development.

Diabetes and the risk of biochemical recurrence in patients with treated localized prostate cancer: a meta-analysis.

BACKGROUND: Biochemical recurrence (BCR), or an elevation in prostate-specific antigen in men after treatment for localized prostate cancer, is an early indication of clinical progression, distant metastases, and mortality. Correlations have also recently been established between diabetes and the incidence and mortality of prostate cancer. However, it remains unknown whether diabetes may predict BCR. METHODS: We performed a meta-analysis of published articles to investigate the prognostic value of diabetes for BCR in prostate cancer. Eight studies and 11,923 patients were included in our meta-analysis. The relative risk (RR) and its 95 % confidence interval (CI) were calculated. RESULTS: We found no apparent association between diabetes and BCR (adjusted RR 1.04; 95 % CI 0.87-1.22). CONCLUSIONS: The evidence of this meta-analysis indicates that diabetes is not a predictor of risk of BCR in patients with prostate cancer.

Differentiation between genetic mutations of breast cancer by breath volatolomics.

Mapping molecular sub-types in breast cancer (BC) tumours is a rapidly evolving area due to growing interest in, for example, targeted therapy and screening high-risk populations for early diagnosis. We report a new concept for profiling BC molecular sub-types based on volatile organic compounds (VOCs). For this purpose, breath samples were collected from 276 female volunteers, including healthy, benign conditions, ductal carcinoma in situ (DCIS) and malignant lesions. Breath samples were analysed by gas chromatography mass spectrometry (GC-MS) and artificially intelligent nanoarray technology. Applying the non-parametric Wilcoxon/Kruskal-Wallis test, GC-MS analysis found 23 compounds that were significantly different (p < 0.05) in breath samples of BC patients with different molecular sub-types. Discriminant function analysis (DFA) of the nanoarray identified unique volatolomic signatures between cancer and non-cancer cases (83% accuracy in blind testing), and for the different molecular sub-types with accuracies ranging from 82 to 87%, sensitivities of 81 to 88% and specificities of 76 to 96% in leave-one-out cross-validation. These results demonstrate the presence of detectable breath VOC patterns for accurately profiling molecular sub-types in BC, either through specific compound identification by GC-MS or by volatolomic signatures obtained through statistical analysis of the artificially intelligent nanoarray responses.

Severe and fatal adverse events risk associated with rituximab addition to B-cell non-Hodgkin's lymphoma (B-NHL) chemotherapy: a meta-analysis.

PURPOSE: Rituximab is a monoclonal antibody targetting the CD20 antigen with the ability to increase overall remission (OR) in B-cell non-Hodgkin's lymphoma (B-NHL). A systematic review and meta-analysis were conducted to determine the risk of the most clinically relevant severe and fatal adverse events (AEs) associated with the use of rituximab in the treatment of B-NHL. PATIENTS AND METHODS: We included phase III clinical trials that used chemotherapy in combination with rituximab or chemotherapy alone as for B-NHL. Statistical analyses were conducted to calculate summary risk ratio (RR) of the relevant severe and fatal AEs related with rituximab. RESULTS: Eight randomised controlled clinical trials were included in this meta-analysis. Summary RR obtained showed no statistically significant rituximab-associated increased risk in 13 severe adverse events (SAEs) (infection, fever, anaemia, thrombocytopaenia, granulocytopenia, liver toxicity, cardiac toxicity, neurologic toxicity, lung toxicity, mucositis, nausea/vomiting, diarrhoea, alopecia) except leukocytopenia (36.4% versus 31%; RR = 1.13; 95%CI, 1.01-1.27; P = 0.03). The incidences of fatal AEs showed noteworthy difference between rituximab group and control group (RR = 1.45; 95% CI, 1.04-2.02; P = 0.03). CONCLUSION: This meta-analysis indicates that there was no proof of statistically higher incidence of most SAEs in rituximab containing group compared with chemotherapy alone. However, fatal infections were more frequently observed in patients who received rituximab. Considering the low-incidence infection-induced death during the treatment period, the effects of rituximab on infections need further investigation.

Assessment of ovarian cancer conditions from exhaled breath.

We present a pilot study that aims to examine the possibility to easily and noninvasively detect and discriminate females with ovarian cancer (OC) from females that have no tumor(s) and from females that have benign genital tract neoplasia, using exhaled breath samples. The study is based on clinical samples and data from 182 females, as follows: 48 females with OC, 48 tumor-free controls and 86 females with benign gynecological neoplasia. Analysis of the breath samples with gas chromatography linked with mass spectrometry shows that decanal, nonanal, styrene, 2-butanone and hexadecane could serve as potential volatile markers for OC. Analysis of the same samples with tailor-made nanoarrays shows good discrimination between females with OC and females that have either no tumor or benign genital tract neoplasia (71% for accuracy, sensitivity and specificity). Conversely, the nanoarray output shows excellent discrimination between the OC patients and the tumor-free controls (79% sensitivity, 100% specificity and 89% accuracy). These results suggest that the nanoarray approach might be useful to avoid unnecessary complicated or expensive tests for tumor-free females in case of a negative result. In the case of positive result, the test will indicate with high probability the presence of OC.