Insights on E1-like enzyme ATG7: functional regulation and relationships with aging-related diseases.

Autophagy is a dynamic self-renovation biological process that maintains cell homeostasis and is responsible for the quality control of proteins, organelles, and energy metabolism. The E1-like ubiquitin-activating enzyme autophagy-related gene 7 (ATG7) is a critical factor that initiates classic autophagy reactions by promoting the formation and extension of autophagosome membranes. Recent studies have identified the key functions of ATG7 in regulating the cell cycle, apoptosis, and metabolism associated with the occurrence and development of multiple diseases. This review summarizes how ATG7 is precisely programmed by genetic, transcriptional, and epigenetic modifications in cells and the relationship between ATG7 and aging-related diseases.

ATM-CHK2-TRIM32 axis regulates ATG7 ubiquitination to initiate autophagy under oxidative stress.

Oxidative stress-induced autophagy helps to prevent cellular damage and to maintain homeostasis. However, the regulatory pathway that initiates autophagy remains unclear. We previously showed that reactive oxygen species (ROS) function as signaling molecules to activate the ATM-CHK2 pathway and promote autophagy. Here, we find that the E3 ubiquitin ligase TRIM32 functions downstream of ATM-CHK2 to regulate ATG7 ubiquitination. Under metabolic stress, ROS induce ATM phosphorylation at S1981, which in turn phosphorylates CHK2 at T68. We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy. In addition, Chk2-/- mice show an aggravated infarction phenotype and reduced phosphorylation of TRIM32 and ubiquitination of ATG7 in a stroke model. We propose a molecular mechanism for autophagy initiation by ROS via the ATM-CHK2-TRIM32-ATG7 axis to maintain intracellular homeostasis and to protect cells exposed to pathological conditions from stress-induced tissue damage.

Expression and regulatory network of E3 ubiquitin ligase NEDD4 family in cancers.

NEDD4 family represent an important group of E3 ligases, which regulate various cellular pathways of cell proliferation, cell junction and inflammation. Emerging evidence suggested that NEDD4 family members participate in the initiation and development of tumor. In this study, we systematically investigated the molecular alterations as well as the clinical relevance regarding NEDD4 family genes in 33 cancer types. Finally, we found that NEDD4 members showed increased expression in pancreas cancer and decreased expression in thyroid cancer. NEDD4 E3 ligase family genes had an average mutation frequency in the range of 0-32.1%, of which HECW1 and HECW2 demonstrated relatively high mutation rate. Breast cancer harbors large amount of NEDD4 copy number amplification. NEDD4 family members interacted proteins were enriched in various pathways including p53, Akt, apoptosis and autophagy, which were confirmed by further western blot and flow cytometric analysis in A549 and H1299 lung cancer cells. In addition, expression of NEDD4 family genes were associated with survival of cancer patients. Our findings provide novel insight into the effect of NEDD4 E3 ligase genes on cancer progression and treatment in the future.

De-ubiquitination of SAMHD1 by USP7 promotes DNA damage repair to overcome oncogenic stress and affect chemotherapy sensitivity.

Oncogenic stress induces DNA damage repair (DDR) that permits escape from mitotic catastrophe and allows early precursor lesions during the evolution of cancer. SAMHD1, a dNTPase protecting cells from viral infections, has been recently found to participate in DNA damage repair process. However, its role in tumorigenesis remains largely unknown. Here, we show that SAMHD1 is up-regulated in early-stage human carcinoma tissues and cell lines under oxidative stress or genotoxic insults. We further demonstrate that de-ubiquitinating enzyme USP7 interacts with SAMHD1 and de-ubiquitinates it at lysine 421, thus stabilizing SAMHD1 protein expression for further interaction with CtIP for DDR, which promotes tumor cell survival under genotoxic stress. Furthermore, SAMHD1 levels positively correlates with USP7 in various human carcinomas, and is associated with an unfavorable survival outcome in patients who underwent chemotherapy. Moreover, USP7 inhibitor sensitizes tumor cells to chemotherapeutic agents by decreasing SAMHD1 in vitro and in vivo. These findings suggest that de-ubiquitination of SAMHD1 by USP7 promotes DDR to overcome oncogenic stress and affect chemotherapy sensitivity.

Role of K63-linked ubiquitination in cancer.

Ubiquitination is a critical type of post-translational modifications, of which K63-linked ubiquitination regulates interaction, translocation, and activation of proteins. In recent years, emerging evidence suggest involvement of K63-linked ubiquitination in multiple signaling pathways and various human diseases including cancer. Increasing number of studies indicated that K63-linked ubiquitination controls initiation, development, invasion, metastasis, and therapy of diverse cancers. Here, we summarized molecular mechanisms of K63-linked ubiquitination dictating different biological activities of tumor and highlighted novel opportunities for future therapy targeting certain regulation of K63-linked ubiquitination in tumor.

Non-Canonical Programmed Cell Death in Colon Cancer.

Programmed cell death (PCD) is an evolutionarily conserved process of cell suicide that is regulated by various genes and the interaction of multiple signal pathways. Non-canonical programmed cell death (PCD) represents different signaling excluding apoptosis. Colon cancer is the third most incident and the fourth most mortal worldwide. Multiple factors such as alcohol, obesity, and genetic and epigenetic alternations contribute to the carcinogenesis of colon cancer. In recent years, emerging evidence has suggested that diverse types of non-canonical programmed cell death are involved in the initiation and development of colon cancer, including mitotic catastrophe, ferroptosis, pyroptosis, necroptosis, parthanatos, oxeiptosis, NETosis, PANoptosis, and entosis. In this review, we summarized the association of different types of non-canonical PCD with tumorigenesis, progression, prevention, treatments, and prognosis of colon cancer. In addition, the prospect of drug-resistant colon cancer therapy related to non-canonical PCD, and the interaction between different types of non-canonical PCD, was systemically reviewed.

The Involvement of TRIB3 and FABP1 and Their Potential Functions in the Dynamic Process of Gastric Cancer.

Background: Dysregulated expression of TRIB3 and FABP1 have been previously observed in human cancer tissues. However, there are little information as to their expression change in dynamic gastric diseases and the functional roles. Methods: Tissues from a total of 479 patients, including 89 GS, 102 IM-GA, 144 EGC, and 144 AGC were collected. The protein expressions of TRIB3 and FABP1 were detected by immunohistochemical staining. Meanwhile, the potential functions of TRIB3 and FABP1 in GC were further analyzed by R software and some internet public databases, such as TCGA and DAVID. Results: During this multi-stage process that go through GS to EGC, the expression trend of TRIB3 and FABP1 protein was GS > IM-GA > EGC. Besides, the expression of TRIB3 protein continued to decrease in AGC, while the expression of FABP1 was abnormally increased. Hp infection was significantly associated with the decreased expression of TRIB3 and FABP1. In addition, the diagnostic efficiency of the combination of these two indicators to diagnose EGC was higher than that of a single indicator. Survival analysis showed that higher expression of TRIB3 or FABP1 could indicate a better prognosis of GC. The protein expressions of TRIB3 and FABP1 were significantly positively correlated. Moreover, CEACAM5 and PRAP1 were positively correlated with both TRIB3 and FABP1 expressions, while GABRP and THBS4 were negatively correlated. The macrophages M0 infiltration was positively correlated with both TRIB3 and FABP1 expressions. Conclusion: The protein expressions of TRIB3 and FABP1 gradually decreased with the gastric disease progress, and was positively correlated. Hp infection may reduce the protein expression of TRIB3 and FABP1. Combing TRIB3 and FABP1 expressions can improve the diagnostic efficiency for EGC. Either a high expression of TRIB3 or FABP1 indicates a better prognosis for GC. TRIB3 and FABP1 may interact with CEACAM5, PRAP1, GABRP and THBS4, and affect tumor immune microenvironment by regulating immune cells, and participate in the development and progression of GC.

Interleukin 20 receptor A expression in colorectal cancer and its clinical significance.

BACKGROUND: Interleukin 20 receptor A (IL20RA) has been shown to play a role in the establishment and progression of multiple tumors. However, the expression of this protein in colorectal cancer (CRC) and its correlation with the clinicopathological parameters of CRC have remained unclear. METHODS: A total of 323 paraffin sections including CRC tissues and adjacent normal tissues after surgery were collected. IL20RA protein expression was detected by immunohistochemical staining. The difference expression of IL20RA mRNA between CRC and normal tissues was also explored in the Oncomine and GEO databases. In addition, the IL20RA-related differentially expressed genes were analyzed in TCGA database and enrichment analysis was conducted to explore the cell functions and pathways related to IL20RA expression. RESULTS: There was increased IL20RA expression in CRC compared with that in normal tissues. High IL20RA expression was associated with greater tumor diameter, lymph node metastasis, and poor TNM stage in CRC, while also being suggestive of poor prognosis. The main pathways of IL20RA-related differentially expressed genes in TCGA were protein heterodimerization activity, oxygen binding, oxygen transporter activity, hormone activity, and lipid transporter activity. Meanwhile, IL20RA-related differentially expressed genes were mainly enriched in peroxidase, nucleotide stimulant repair, fatty acid metabolism, basal transcription factor, and RNA degradation. CONCLUSIONS: IL20RA might have a role as a biomarker for CRC. Its upregulation might contribute to an aggressive phenotype in CRC. IL20RA's involvement in the development and progression of CRC might occur through it affecting fatty acid metabolism, oxygen binding, oxygen transport, and hormone activity.

Integrative analysis of somatic mutations and differential expression profiles in glioblastoma based on aging acceleration.

BACKGROUND: Glioblastoma (GBM) is an aggressive brain tumor and the mechanisms of progression are very complex. Accelerated aging is a driving factor of GBM. However, there has not been thorough research about the mechanisms of GBM progression based on aging acceleration. METHODS: The aging predictor was modeled based on normal brain samples. Then an aging acceleration background network was constructed to explore GBM mechanisms. RESULTS: The accelerated aging-related mechanisms provided an innovative way to study GBM, wherein integrative analysis of somatic mutations and differential expression revealed key pathologic characteristics. Moreover, the influence of the immune system, the nervous system and other critical factors on GBM were identified. The survival analysis also disclosed crucial GBM markers. CONCLUSION: An integrative analysis of multi-omics data based on aging acceleration identified new driving factors for GBM.

XPF expression and its relationship with the risk and prognosis of colorectal cancer.

BACKGROUND: XPF (xeroderma pigmentosum complementation group F) is a key factor contributing to DNA damage excision of nucleotide excision repair pathway. The relationship between XPF expression and the risk and prognosis of colorectal cancer (CRC) is unclear. METHODS: In this experiment, a total of 824 cases of colorectal tissue were collected. XPF protein expression was detected by immunohistochemical staining. We conducted a Mann-Whitney U test in order to explore the differential expression of XPF between CRC and non-cancer controls, and the correlation between XPF expression and CRC clinicopathological parameters. Univariate and multivariate Cox regression analyses were conducted to investigate the relationship between XPF expression and CRC prognosis. The Java based software GSEA as well as STRING, David, GO, KEGG were used to explore the function and regulation network of XPF. RESULTS: The results demonstrated that the XPF expression in CRC was significantly up-regulated compared with non-tumor controls (P < 0.001) and adenoma tissue (P < 0.001). XPF protein was increased in the dynamic sequence of anal diseases to adenoma tissue to CRC. Expression of XPF was related to tumor location (P = 0.005) and tumor growth pattern (P = 0.009). The results of prognosis analysis suggested that in patients with stage T1-T2, XPF low expression may be significantly associated with better overall survival (HR = 7.978, 95% CI 1.208-52.673, P = 0.031). XPF and its interacting genes played a vital role in different processes of nucleotide excision repair pathway. XPF expression was related with Ubiquitin like protein specific protease activity. CONCLUSIONS: XPF might be a promising biomarker for CRC risk, and also showed potential as a prognostic predictor in CRC patients.

Comprehensive analysis of ceRNA network of ERCC4 in colorectal cancer.

OBJECTIVE: ERCC4 is one of the most significant molecules of Nucleotide Excision Repair (NER), which has been researched due to its high expression in colorectal cancer (CRC). This study aimed to find out the ceRNA (competitive endogenous RNA) network of ERCC4 in CRC. METHODS AND MATERIALS: Pan cancer mRNA expression of ERCC4 was evaluated using TCGA database. The protein expression of ERCC4 was evaluated based on the Human Protein Atlas (HPA). We screened DElncRNAs and DEmiRNAs in two groups of ERCC4 high and ERCC4 low expression in CRC. Then a lncRNA-miRNA-ERCC4 regulatory network was constructed based on DElncRNAs and DEmiRNAs using Starbase database and visualized by Cytoscape software. Kaplan-Meier analysis was performed to evaluate the prognostic value of the ceRNA network. Further, RT-PCR was performed to validate the expression of the representative molecules in the ceRNA network in CRC and normal tissues. The relationship between drug sensitivity and these molecules were also evaluated using RNAactDrug database. RESULTS: ERCC4 was overexpressed in a variety of tumors at mRNA levels, including CRC. High expression of ERCC4 was also observed on protein level in CRC. A total of 1,885 DElncRNAs and 68 DEmiRNAs were identified from CRC samples in ERCC4 high and ERCC4 low expression groups. Predicted by the Starbase database, we got interacting miRNAs and lncRNAs of ERCC4 from the DEmiRNAs and DElncRNAs, and a lncRNA-miRNA-ERCC4 regulatory network was constructed. Kaplan-Meier survival curves results showed that miR-200c-3p (hazard ratio [HR] = 0.62, P = 0.032), MALAT1 (HR = 1.54, P = 0.016), and AC005520.2 (hazard ratio [HR] = 1.75, P = 0.002) were significantly associated with the prognosis of CRC. After validation by RT-PCR, we found that ERCC4 and MALAT1 were up-regulated in CRC compared with normal tissues, while miR-200c-3p was down-regulated. A strong negative correlation was observed between MALAT1 and miR-200c-3p. Drug sensitivity analysis showed that ERCC4, miR-200c and MALAT1 were all associated with Cisplatin. CONCLUSION: We constructed a ceRNA network of ERCC4 in CRC, of which the MALAT1-miR-200c-3p-ERCC4 axis may be involved in the development, prognosis and chemotherapy sensitivity of CRC. These findings might provide novel clues and insights on the molecular mechanisms of ERCC4 and NER pathway in CRC.

Differentially Expressed mRNAs and Their Long Noncoding RNA Regulatory Network with Helicobacter pylori-Associated Diseases including Atrophic Gastritis and Gastric Cancer.

BACKGROUND: Helicobacter pylori (Hp) infection is the strongest risk factor for gastric cancer (GC). However, the mechanisms of Hp-associated GC remain to be explored. METHODS: The gene expression profiling (GSE111762) data were downloaded from the GEO database. Differentially expressed genes (DEGs) between normal samples (NO) and Hp-atrophic gastritis (GA) or Hp-GA and Hp-GC were identified by GEO2R. Gene Ontology and pathway enrichment analysis were performed using the DAVID database. lncRNA-TF-mRNA and ceRNA regulation networks were constructed using Cytoscape. The cross-networks were obtained by overlapping molecules of the above two networks. GSE27411 and GSE116312 datasets were employed for validation. RESULTS: DEGs between NO and Hp-GA are linked to the activity of inward rectifying potassium channels, digestion, etc. DEGs between Hp-GA and Hp-GC were associated with digestion, positive regulation of cell proliferation, etc. According to the lncRNA-TF-mRNA network, 63 lncRNAs, 12 TFs, and 209 mRNAs were involved in Hp-GA while 16 lncRNAs, 11 TFs, and 92 mRNAs were contained in the Hp-GC network. In terms of the ceRNA network, 120 mRNAs, 18 miRNAs, and 27 lncRNAs were shown in Hp-GA while 72 mRNAs, 8 miRNAs, and 1 lncRNA were included in the Hp-GC network. In the cross-network, we found that immune regulation and differentiation regulation were important in the process of NO-GA. Neuroendocrine regulation was mainly related to the process of GA-GC. In the end, we verified that CDX2 plays an important role in the pathological process of NO to Hp-GA. Comparing Hp-GA with Hp-GC, DEGs (FPR1, TFF2, GAST, SST, FUT9, and SHH), TF, and GATA5 were of great significance. CONCLUSIONS: We identified the DEGs, and their lncRNA regulatory network of Hp-associated diseases might provide insights into the mechanism between Hp infection and GC. Furthermore, in-depth studies of the molecules might be useful to explore the multistep process of gastric diseases.

Joint analysis of lncRNA m6A methylome and lncRNA/mRNA expression profiles in gastric cancer.

BACKGROUND: N 6-methyladenosine (m6A) modification might be closely associated with the genesis and development of gastric cancer (GC). Currently, the evidence established by high-throughput assay for GC-related m6A patterns based on long non-coding RNAs (lncRNAs) remains limited. Here, a joint analysis of lncRNA m6A methylome and lncRNA/mRNA expression profiles in GC was performed to explore the regulatory roles of m6A modification in lncRNAs. METHODS: Three subjects with primary GC were enrolled in our study and paired sample was randomly selected from GC tissue and adjacent normal tissue for each case. Methylated RNA Immunoprecipitation NextGeneration Sequencing (MeRIP-Seq) and Microarray Gene Expression Profiling was subsequently performed. Then co-expression analysis and gene enrichment analysis were successively conducted. RESULTS: After data analysis, we identified 191 differentially m6A-methylated lncRNAs, 240 differentially expressed lncRNAs and 229 differentially expressed mRNAs in GC. Furthermore, four differentially m6A-methylated and expressed lncRNAs (dme-lncRNAs) were discovered including RASAL2-AS1, LINC00910, SNHG7 and LINC01105. Their potential target genes were explored by co-expression analysis. And gene enrichment analysis suggested that they might influence the cellular processes and biological behaviors involved in mitosis and cell cycle. The potential impacts of these targets on GC cells were further validated by CCLE database and literature review. CONCLUSIONS: Four novel dme-lncRNAs were identified in GC, which might exert regulatory roles on GC cell proliferation. The present study would provide clues for the lncRNA m6A methylation-based research on GC epigenetic etiology and pathogenesis.

Profiles of PD-1, PD-L1, PD-L2 in Gastric Cancer and Their Relation with Mutation, Immune Infiltration, and Survival.

BACKGROUND: Although multiple types of cancers demonstrated favorable outcome after immunotherapy of PD-1/PD-L1 blockade, the specific regulatory mechanism of PD genes in gastric cancer (GC) remains largely unknown. MATERIALS AND METHODS: Expression of RNA, copy number variants, and clinical parameters of GC individuals from TCGA were analyzed. Coexpressed genes for PD-1, PD-L1, and PD-L2 were selected by correlation analysis and confirmed by STRING. Gene Ontology and KEGG pathway analyses were performed by clusterProfiler. The influence of PD-1/PD-L1/PD-L2 on immune cell infiltration was investigated by MCP-counter. RESULTS: PD-L2 demonstrated significant relation with clinical stage of GC (P = 0.043). Survival analysis showed that PD-1 expression was correlated with better prognosis of GC patients (HR = 0.70, P = 0.031), but PD-L2 expression was related with worse survival (HR = 1.42, P = 0.032). Mutation of PIK3CA could alter the level of PD-1, PD-L1, and PD-L2 (P < 0.001), and TP53 mutation demonstrated significant correlation with PD-L1 (P = 0.015) and PD-L2 (P = 0.014) expression. Enrichment analysis of PD-1/PD-L1/PD-L2 coexpressed genes indicated a biological process of mononuclear cell proliferation, leukocyte cell-cell adhesion, and lymphocyte activation as well as KEGG pathways including cell differentiation of Th1 and Th2, cell differentiation of Th17, and hematopoietic cell landscape. As for immune infiltration analysis, PD-1 was mainly related with cytotoxic lymphocytes and endothelial cells; PD-L1 were associated with monocytic lineage; PD-L2 showed significant correlation with myeloid dendritic cells. CONCLUSION: PD-1 expression showed association with better prognosis of GC, and PD-L2 expression was related with worse survival. Mutations of PIK3CA and TP53 significantly correlated with PD-1/PD-L1/PD-L2 axis. PD-1/PD-L1/PD-L2 coexpressed genes demonstrated enrichment in mononuclear cell proliferation, leukocyte cell-cell adhesion, and lymphocyte activation as well as KEGG pathways including cell differentiation of Th1, Th2, and Th17.

RNF8 induces ß-catenin-mediated c-Myc expression and promotes colon cancer proliferation.

DNA damage signals transducer RING finger protein 8 (RNF8) is involved in maintaining genomic stability by facilitating the repair of DNA double-strand breaks (DSB) via ubiquitin signaling. By analyzing the TCGA database and colon cancer tissue microarrays, we found that the expression level of RNF8 was positively correlated with that of c-Myc in colon cancer, which were closely associated with poor survival of colon cancer patients. Furthermore, overexpressing and knocking down RNF8 increased and decreased the expression of c-Myc in colon cancer cells, respectively. In addition, RNF8 interacted with ß-catenin and facilitated its nuclear translocation by conjugating K63 polyubiquitination on it. These observations suggested a de novo role of RNF8 in promoting the progression of colon cancer by inducing ß-catenin-mediated c-Myc expression.

Prognostic evaluation of colorectal cancer using three new comprehensive indexes related to infection, anemia and coagulation derived from peripheral blood.

Background: Many indicators of peripheral blood in routine blood test (BRT) results of colorectal cancer (CRC) patients are related to prognosis. Currently, indexes such as NLR (Neutrophil-to- Lymphocyte Ratio), PLR (Platelet-to-Lymphocyte Ratio) and LMR (Lymphocyte-to-Monocyte ratio) evaluate the survival risk of patients by assessing the inflammatory - immune status of CRCs. These indexes are more comprehensive and accurate than independent estimates. We hope to design more effective indexes through fully considering the correlation and significance between BRT indicators and prognosis, so as to play a guiding role in clinical malignant estimation of CRCs. Methods: 701 CRCs in training set and 256 CRCs in test set were included in the study samples, and their clinical data, tumor pathology results and peripheral blood routine results were collected. The prognosis, progression, and survival status of all patients were determined after follow-up. Above data were used for statistical analysis and designing new indexes. Results: It was found that high NE, MONO, RDW-CV/SD and PLT in peripheral blood indicated poor prognosis of DFS and OS. Conversely, CRCs with postoperative tumor progression or death had lower LY, EO, RBC, HGB, HCT, MCV, MCH, MCHC, PDW, and P-LCR. IRR, ARR and CRR related to infection, anemia and coagulation were designed respectively using the largest AUC indicators (P<0.05) selected by ROC curve. The formula: IRR= (NE*MONO)/(LY*EO); ARR= (HGB*MCHC)/RDW-CV; CRR=PLT/PDW. Results of Kaplan­Meier survival analysis and multivariate COX proportional hazard analysis adjusted for age, gender, TNM stage, infiltration, adhesion showed IRR, ARR, CRR were all able to be used as the evaluation standard of survival of CRC. The result was also authenticated in the test set. Conclusion: We designed three different prognostic indexes of colorectal cancer, IRR, ARR and CRR, which could be used as risk indicators of CRC prognosis, tumor progression and survival.

A Systematic Review and Meta-Analysis for the Association of Gene Polymorphisms in RAN with Cancer Risk.

As an important component of miRNA processing genes, RAN gene encodes the ras-related nuclear protein, which is a unique member of the Ras superfamily of GTPases. The mutations in RAN gene are very likely to play a critical role in pathology-related changes to miRNA transport and expression and thus participate in tumor genesis and development. Currently, accumulating studies have explored the association between RAN SNPs and cancer risk. However, the results are conflicting. In the present study, we performed a systematic review for the association of RAN SNPs with overall cancer risk. Meanwhile, a meta-analysis was conducted based on available data, aiming at clarifying the association between RAN SNPs and cancer susceptibility. After literature search and data extraction, 17 studies containing four RAN SNPs were involved in the systematic review. And 12 studies with two highly studied SNPs (RAN rs14035 C>T and rs3803012 A>G) were included in the final meta-analysis, consisting of 7662 cases and 9807 controls. The results showed that the rs14035 polymorphism was linked to a decreased cancer risk in overall subjects and hospital-based (HB) subgroup, while the rs3803012 polymorphism conferred to an increased cancer risk in overall subjects and population-based (PB) subgroup. Our findings suggested that the two SNPs had the potential to be predictive biomarkers for cancer risk. The study would provide novel clues for the identification of miRNA-related genetic biomarkers applied to predicting cancer susceptibility.

Nucleotide excision repair pathway gene polymorphisms are associated with risk and prognosis of colorectal cancer.

BACKGROUND: Single nucleotide polymorphisms (SNPs) are universally present in nucleotide excision repair (NER) pathway genes, which could make impacts on colorectal carcinogenesis and prognosis. AIM: To explore the association of all tagSNPs in NER pathway genes with colorectal cancer (CRC) risk and prognosis in a northern Chinese population by a two-stage case-control design composed of a discovery and validation stage. METHODS: Genotyping for NER SNPs was performed using kompetitive allele specific PCR. In the discovery stage, 39 tagSNPs in eight genes were genotyped in 368 subjects, including 184 CRC cases and 184 individual-matched controls. In the validation stage, 13 SNPs in six genes were analyzed in a total of 1712 subjects, including 854 CRC cases and 858 CRC-free controls. RESULTS: Two SNPs (XPA rs10817938 and XPC rs2607775) were associated with an increased CRC risk in overall and stratification analyses. Significant cumulative and interaction effects were also demonstrated in the studied SNPs on CRC risk. Another two SNPs (ERCC2 rs1052555 and ERCC5 rs2228959) were newly found to be associated with a poor overall survival of CRC patients. CONCLUSION: Our findings suggest novel SNPs in NER pathway genes that can be predictive for CRC risk and prognosis in a large-scale Chinese population. The present study has referential values for the identification of all-round NER-based genetic biomarkers in predicting the susceptibility and clinical outcome of CRC.

MiR-1539 and Its Potential Role as a Novel Biomarker for Colorectal Cancer.

PURPOSE: We investigated microRNA (miR) 1539 as a potential biomarker for predicting the risk and pathobiological behavior of colorectal cancer (CRC). METHODS: Our strategy consisted of analyzing 100 serum samples from 51 CRC patients, 49 healthy controls (HCs), and another 56 CRC tissue and matched normal adjacent to tumor (NAT) samples. The relative expression levels of miR-1539 in exosomes, serum and tissues were detected and compared in the different groups, using reverse transcription-polymerase chain reaction (RT-qPCR). The diagnostic value and potential function of miR-1539 were investigated using clinicopathological data combined with bioinformatics analysis. RESULTS: MiR-1539 expression was significantly up-regulated in exosomes (p = 0.003) and cancer tissue (p < 0.001) from CRC patients. MiR-1539 expression levels in serum varied according to different tumor sites (right-sided vs. left-sided, p = 0.047; left-side CRC vs. HCs, p = 0.031). In terms of diagnostic efficacy, miR-1539 expression in exosomes may help distinguish CRC cases from HCs with a sensitivity of 92.2%, and miR-1539 expression in serum may improve the specificity to 96.6% for left-sided CRC diagnosis. When combined with clinicopathological data, serum miR-1539 levels were positively associated with vascular endothelial growth factor (VEGF) expression (p = 0.028), whilst levels in CRC tissue were positively associated with increased Ki-67 levels (p = 0.035). Poorer pathologic differentiation was potentially related to an increased tendency of miR-1539 expression in CRC tissue (p = 0.071). Based on our bioinformatics analysis, miR-1539 may have a significant mechanistic influence on CRC genesis and progression. CONCLUSIONS: Circulating or tissue based miR-1539 may be used as a novel potential biomarker for CRC screening, and a predictor of poor clinicopathological behavior in tumors.

Preoperative insomnia and its association with psychological factors, pain and anxiety in Chinese colorectal cancer patients.

PURPOSE: Sleep disturbances are common in cancer patients, but little is known about preoperative insomnia and its associated factors in colorectal cancer (CRC) patients. The aim of this study was to clarify the relationship between preoperative insomnia and its associated factors (i.e., pain, anxiety, self-esteem, and coping styles) in CRC patients. METHODS: A cross-sectional study was conducted in consecutive CRC inpatients (N = 434), who were required to complete the questionnaires about insomnia, pain, anxiety, self-esteem, and coping styles (acceptance/resignation, confrontation, avoidance) before the day of surgery. Hierarchical regression analyses were conducted to explore the relationships between preoperative anxiety and its associated factors. RESULTS: Based on the cutoff value of Athens Insomnia Scale (scores ≥ 6) in Chinese cancer patients, the prevalence of insomnia was 38.2% before surgery. Pain (ß = 0.087, p = 0.015) and anxiety (ß = 0.372, p < 0.001) were positively associated with preoperative insomnia, while self-esteem (ß = - 0.479, p < 0.001) and confrontation coping (ß = - 0.124, p = 0.003) showed protective effects on preoperative insomnia when putting them together into hierarchical regression. The associated factors together accounted for an additional variance of preoperative insomnia (47.6%). CONCLUSIONS: In line with previous findings, the detrimental effects of pain and anxiety on preoperative insomnia were also observed in our study. More importantly, our main new findings were that self-esteem and confrontation coping played important roles in alleviating preoperative insomnia among CRC patients. Clinicians should take these results into account when developing cancer care management to relieve preoperative insomnia.